Out of the frying pan and into the fire: damage-associated molecular patterns and cardiovascular toxicity following cancer therapy

Abstract

Cardio-oncology is a new and rapidly expanding field that merges cancer and cardiovascular disease. Cardiovascular disease is an omnipresent side effect of cancer therapy; in fact, it is the second leading cause of death in cancer survivors after recurrent cancer. It has been well documented that many cancer chemotherapeutic agents cause cardiovascular toxicity. Nonetheless, the underlying cause of cancer therapy-induced cardiovascular toxicity is largely unknown. In this review, we discuss the potential role of damage-associated molecular patterns (DAMPs) as an underlying contributor to cancer therapy-induced cardiovascular toxicity. With an increasing number of cancer patients, as well as extended life expectancy, understanding the mechanisms underlying cancer therapy-induced cardiovascular disease is of the utmost importance to ensure that cancer is the only disease burden that cancer survivors have to endure.

Keywords

cancer therapy cardio-oncology cardiotoxicity cardiovascular disease damage-associated molecular patterns inflammation

Introduction

Cancer therapy has advanced dramatically in such a way that not only do cancer patients have increased life expectancy, they also have increased survival rates.¹ Currently, there are 15.5 million patients living beyond a cancer diagnosis and by 2026, that number is estimated to increase to 20.3 million.¹ However, stemming from both short- and long-term cancer treatment, which is often given in multi-drug combinations and escalating doses, new problems are emerging.² One such problem is cardiovascular complications, which is the second leading cause of death in cancer survivors, only after cancer recurrence, cancer progression, and secondary malignancies.³ In fact, cardiovascular complications have become so prominent that a new area of research is emerging within both cardiology and oncology to prevent and treat cancer therapy-induced cardiotoxicity; this field is referred to as cardio-oncology.

Interestingly, several studies have demonstrated a poor correlation between traditional cardiovascular risk factors such as obesity, dyslipidemia, insulin resistance, and tobacco use, with the onset of cardiovascular disease in cancer survivors,^4,5 suggesting an alternative mechanism for systemic cardiovascular toxicity. One such mechanism could be inappropriate immune system activation, which has an active role in both cancer and cardiovascular disease.^6–9 It has been well established that the immune system not only responds to foreign substances (i.e. pathogens), it also responds to endogenously derived molecules that are expressed as a result of tissue damage or stressed cells, known as damage-associated molecular patterns (DAMPs).^10,11 DAMPs are present in both cancer and cardiovascular disease; however, the roles that DAMPs play are not congruent. In cardiovascular disease literature, high and chronic levels of DAMPs have been shown to be inflammogenic and are associated with disease pathogenesis.^12,13 In cancer, the presence of DAMPs has been shown to be a sign of both treatment efficacy and the development of resistance.^14,15

Mechanisms of action for therapies such as chemotherapy and radiation have been proposed and reported in the literature;^16–21 however, due to the underlying goal of cancer therapy to reduce tumor size, we hypothesize that the unintentional release of DAMPs after any cancer therapeutic contributes to the development of cardiovascular disease, including hypertension. This review describes the increased prevalence of cancer therapy-induced cardiotoxicity after cancer therapy and the possible role that DAMPs play in the disease process.

Cancer therapies cause cell death

Cancer is a complex disease due to the ability of cancer cells to adapt to changing environmental conditions guaranteeing growth and survival. Cancer is the result of one or more DNA mutations, genetically predisposed or environmentally acquired, that allow cells to escape the normal mechanisms constraining cell division and growth. Regardless of mutation or cancer type, cancer cells exhibit four main characteristics, (1) uncontrolled proliferation, (2) de-differentiation and loss of function, (3) invasiveness, and (4) metastasis. Cancer therapies are designed to target these abnormal characteristics.

Cancer therapy type and regimen are often determined by factors specific to the patient and tumor characteristics, with the intention to cure, prolong survival, or relieve symptoms. The classic dogma of cancer therapy uses a continuous dosing strategy to ‘kill as many cancer cells as possible’. In this type of treatment strategy, there is a delicate balance amid median effective dose (ED₅₀), lethal dose (LD₅₀), toxicity, and drug resistance.²² Currently, there are research groups and clinical trials studying differing dosing schedules aimed at thwarting tumor evolution.²² Using effective treatment modality, dose, and frequency are several ways clinicians combat this multifaceted disease.²²

The main treatment categories for cancer include surgery, radiation, chemotherapy, hormone therapy, immunotherapy, and targeted therapy, which can be mixed and added together for augmented outcomes. Excluding surgery, which entails the resection of a malignant tumor, all other forms of cancer treatment aim to destroy the pro-proliferative and de-differentiated cancer cells within the body.

Radiation is a form of cancer therapy used mainly against solid tumors. Radiation utilizes high-energy particles or waves to kill cancer cells by inducing irreparable DNA breaks within cells. This method targets rapidly dividing cells; however, its effects may not take place until days or weeks after initiation and cell death could continue months after treatment is completed. Chemotherapy is another form of cancer therapy, which utilizes cytotoxic drugs to treat disseminated cancer; solid tumors are not as sensitive to this treatment option. Chemotherapy targets rapidly growing and dividing cells, and slows tumor proliferation by inhibiting specific aspects of cellular replication, ultimately leading to cell death. As the name implies, targeted therapies are more specific when compared with chemotherapy, and are directed against specific molecules and pathways that drive tumor growth.²³ For example, these types of therapies are normally small molecule inhibitors or monoclonal antibodies that block or turn off chemical signals, modify certain proteins, trigger the immune response, or carry toxic substances to cancer cells, thus resulting in cancer cell death. Targeted therapies often lead to tolerance due to overexpression of the targeted protein or through acquired mutation making the drug useless.²⁴ Immunotherapy reinforces or sensitizes the immune system as a defense against tumors. The main categories of immunotherapy include monoclonal antibody therapy (also considered a targeted therapy), immune checkpoint inhibitors, cancer vaccines, and other nonspecific immunotherapies.²⁵

While there is no doubt cancer therapies are effective at targeting and eliminating cancerous cells within the body and increasing patient survival,¹ these treatments also induce unpleasant and unintended side effects. These side effects not only include those that affect quality of life (e.g. drowsiness, restlessness, anxiety, loss of libido, etc.), they also promote other life-threatening complications, including cardiovascular disease.^3,26 Nonetheless, the mechanisms underlying cancer therapy-induced cardiotoxicity remain relatively unexplored.

Clinical definitions and guidelines for cardiotoxicity after cancer treatment

The National Cancer Institute (NCI) defines cardiotoxicity as ‘toxicity that affects the heart’.²⁷ Aside from this broad definition, there are no universal guidelines for identifying and measuring cancer therapy-induced cardiotoxicity.²⁸ As a result, multiple interpretations of the NCI definition exist. For instance, the NCI Common Terminology Criteria for Adverse Events (CTCAE)²⁹ is considered the standard for clinical trial reporting of adverse events,³⁰ and it includes left ventricular dysfunction (LVD) and heart failure (HF) within its terminology, but does not include hypertension. However, other entities vary in their cardiotoxicity definition. For instance, the Food and Drug Administration (FDA) defines anthracycline cardiotoxicity as >20% decrease in left ventricular ejection fraction (LVEF) when baseline LVEF is normal, or >10% decrease when baseline LVEF is not normal.^28,31 Multiple other studies, including the Herceptin Adjuvant (HERA) trial and the Breast Cancer International Research Group (BCIRG), use different measurements to define cardiotoxicity, although LVD is frequently cited.^32–34

Plana et al.³⁵ offer a more structured classification system for cancer therapy-induced cardiotoxicity, grouping symptoms into two groups, type 1 or type 2. The type 1 category of cardiotoxicity uses doxorubicin as the representative agent and encompasses cancer therapies with dose-dependent side effects and induces irreversible myocardial damage. Type 2 uses trastuzumab as the typical agent: this classification describes cancer therapy side effects that are not dose related and are reversible. Symptoms in each category can then be further classified as symptomatic or asymptomatic. The various definitions and classifications of cardiotoxicity, paired with the lack of knowledge of cancer therapy-specific pathophysiological mechanisms have made it difficult for clinicians to detect and therefore prevent and manage cancer therapy-induced cardiotoxicity.^35,36

Regardless of a lack of universal classification guidelines, there are some established prevention measures in place to combat cancer therapy-induced cardiotoxicity. For example, the American College of Cardiology and American Heart Association have together established procedures for chemotherapeutic agents and radiation therapy that have well described cardiovascular side effects, in order to reduce/prevent them.^37–40 To combat these pathologies, the first line of defense is traditional cardioprotective therapies (e.g. iron chelators, angiotensin-converting enzyme inhibitors (ACE-I), beta-blockers, and statins).⁴¹ In fact, dexrazoxane, an iron chelator, has been found to be cardioprotective in women diagnosed with advanced breast cancer and receiving anthracycline-based chemotherapy.^39,42 Statin therapy has been noted to decrease heart failure incidence in breast cancer patients;⁴³ however, given the potential side effect of rhabdomyolysis, statins should be used with caution.^43,44 While the use of these cardioprotective agents seems to reduce cardiotoxicity,⁴¹ the need for universal guidelines for cardiotoxicity identification, as well as novel prevention and treatment options, is emphasized by the high rates of cardiovascular morbidity and mortality following cancer therapy.²

Evidence for cardiovascular complications after cancer treatment

In the United States, an estimated one in three adults has been diagnosed with hypertension, 15 million people live with cardiovascular disease (e.g. heart failure, arrhythmias, cardiac dysfunction, etc.),⁴⁵ and approximately 14 million individuals have a prior history of cancer.⁹ As the US population ages and cancer prognosis improves, so will the number of patients living with both cardiovascular disease and cancer. Not only is cardiovascular disease a leading cause of death among cancer survivors, there is an elevated risk of developing cardiovascular pathology which approaches 40% of the cancer population.³⁶ The elevated risk of developing cardiovascular disease could be confounded by pre-existing genetic, lifestyle, age, endocrine, and environmental factors unique to each cancer patient (Figure 1). However, these factors, as well as traditional cardiovascular disease risk factors (obesity, dyslipidemia, insulin resistance, and tobacco use),^4,5 do not fully account for the increased incidence of cancer therapy-induced cardiovascular toxicity.¹⁸

Figure 1.

Common risk factors that contribute to both cancer and cardiovascular disease. Adapted from Irvine Page’s Mosaic Theory of Hypertension.⁴⁶

The main cancer therapies reported to induce cardiovascular dysfunction and disease are radiation, vascular endothelial growth factor (VEGF) inhibitors, which encompass tyrosine kinase inhibitors (TKIs) sorafenib and sunitinib, as well as monoclonal antibodies bevacizumab and ramucirumab, human epidermal growth factor receptor type 2 (HER2) monoclonal antibody trastuzumab, and chemotherapeutic agents such as anthracyclines, platinum-based antineoplastic drugs, microtubule inhibitors, and antimetabolites. Cardiotoxicity induced by these agents could be the result of either on-target effects (e.g. tyrosine kinases located on noncancerous vascular cells) or off-target effects (e.g. implicating pathways of vascular cells differently from cancerous cells) of cancer therapies.²³ The time-dependent effects of cancer therapy-induced cardiotoxicity vary according to the specific therapy and the patients’ baseline measurements. Table 1 lists the major forms of cancer therapy and summarizes their reported cardiovascular side effects, as well as their proposed mechanisms.

Table 1.

Common cardiovascular side effects of cancer therapy and potential mechanisms leading to dysfunction.

Class	Drug	Drug target	Cardiovascular side effects	Potential Mechanism
Radiation	NA	Rapidly growing cells	Pericarditis, hypertension, cardiomyopathy, myocardial fibrosis, coronary artery disease, pericardial effusion, valvular disease, arrhythmias,²⁰ autonomic dysfunction⁴⁷	Fibrosis, endothelial cell damage,²⁰ oxidative stress⁴⁸
Chemotherapy
Alkylating agents	Carboplatin, cisplatin, cyclophosphamide, oxaliplatin, ifosfamide	Rapidly growing cells; intrastrand cross-linking of DNA	Hypertension, myocardial ischemia,⁴⁹ thromboembolism, cerebrovascular disease,¹⁸ myocardial infarction, cardiomyopathy,⁵⁰ pericarditis¹⁶	Oxidative stress,^51,52 endothelial dysfunction, platelet activation,¹⁸ upregulation of adhesion molecule-1, increased plasminogen activator⁵³
Antimetabolites	5-Fluorouracil, methotrexate, capecitabine, gemcitabine, cytarabine	Rapidly growing cells; blocking DNA/RNA synthesis	Cardiac ischemia^54,55 angina, ECG changes, thrombosis	Oxidative stress, myocardial cell damage and necrosis, endothelial cell damage⁵⁶
Anthracyclines	Daunorubicin, doxorubicin, epirubicin,idarubicin, mitoxantrone	Rapidly growing cells; enzymes involved in DNA replication	Cardiomyopathy, arrhythmia, acute myocarditis,⁵⁷ heart failure,⁵⁸ LVD⁵⁹ cardiac ischemia^60,61	Oxidative stress,^62,63 DNA damage,⁶⁴ topoisomerase 2-alpha,⁶⁵ alterations in ATP production in myocytes, myocyte damage and apoptosis¹⁸
Topoisomerase inhibitors	Topotecan, irinotecan,etoposide, teniposide	Rapidly growing cells; topoisomerase inhibition	Bradycardia,⁶⁶ cardiac toxicity,⁶⁷ cardiac ischemia¹⁶	Topoisomerase 2-a⁶⁸
Mitotic inhibitors	Paclitaxel, docetaxel,estramustine, ixabepilone, vinblastine	Rapidly growing cells; microtubule assembly, inhibition of spindle formation	Myocardial ischemia,⁶⁹ coronary spasm,⁴⁹ arrhythmias, bradycardia, hypertension⁷⁰	Modulation of calcium handling,⁷¹ cellular hypoxia¹⁸
Targeted therapy
Tyrosine kinase inhibitors	Imatinib,dasatinib, nilotinib, bosutinib, ponatinib, sorafenib, sunitinib, lapatinib	ABL1 kinaseKIT, PDGFRα, VEGF⁷²	Cardiomyopathy,^73,74 heart failure,^75–77 hypertension, LVD,¹⁶ thromboembolism, cardiac contractile dysfunction⁷⁸	Inhibiting cell survival, angiogenesis, and cell growth,⁴⁹ inhibition of NO and prostacyclin, increased production of endothelin-1,⁷⁹ oxidative stress, endothelial cell apoptosis,⁸⁰ disruption of mitochondrial metabolism and impairment of myocardial function.⁸¹
Immunotherapy
Interferons, interleukins	Type I-III IFNs	Immune system activation	Hypertension, arrhythmias, heart failure, LVD,¹⁶ myocardial infarction⁸²	PRR activation,⁸³ interferon-induced coronary spasm⁸⁴
Monoclonal antibodies
	Trastuzumab,lapatinib, pertuzumab	HER2	Systolic cardiac dysfunction,^49,85 cardiomyopathy,⁸⁵ reduced LVEF, heart failure, hypertension⁸⁶	Cardiac myocyte dysfunction,⁸⁷ increased sympathetic output,⁸⁶ impaired cardiac repair and myocyte homeostasis⁸⁸
	Bevacizumab, ramucirumab	VEGF	Cardiac ischemia,⁸⁹ heart failure,⁷⁵ systolic dysfunction, left ventricular dysfunction, hypertension,⁸² thromboembolism¹⁶	Cardiac myocyte dysfunction,⁹⁰ inhibiting cell survival, angiogenesis, and cell growth,⁴⁹ inhibition of NO and prostacyclin, increased production of endothelin-1,⁷⁹ oxidative stress, endothelial cell apoptosis⁸⁰

ABL1, Abelson tyrosine-protein kinase 1; ATP, adenosine triphosphate; DNA, deoxyribonucleic acid; ECG, electrocardiogram; HER2, human epidermal growth factor receptor 2; IFN, interferon; KIT, stem cell factor receptor/CD117; LVD, left ventricular dysfunction; LVEF, left ventricular ejection fraction; NO, nitric oxide; PDGFRα, platelet-derived growth factor alpha; PRR, pattern-recognition receptor; RNA, ribonucleic acid; VEGF, vascular endothelial growth factor.

Radiation

Radiation is an effective cancer therapy, nevertheless it has serious cardiovascular side-effects, such that it has been termed radiation-induced heart disease (RIHD) and radiation-induced vascular disease (RIVD).^20,21 These symptoms include pericarditis, cardiomyopathy, myocardial fibrosis, coronary artery disease, peripheral vascular disease, pericardial effusion, valvular disease, arrhythmias, and autonomic dysfunction.^20,47 RIHD can have acute, subacute, and late presentation and may affect the entire cardiovascular system at any stage.²¹ Besides the well-known radiation effects to the heart, medium-sized to large-sized vessels demonstrate lipid accumulation, inflammation, thrombosis, increase in intimal thickness, and connective tissue after exposure.^91,92

Cardiotoxicity, secondary to radiation, is increased in severity and incidence with increasing doses of radiation (i.e. dose dependent), volume of body area exposed, time since exposure, and adjuvant therapies.¹⁹ The cancer therapy-induced cardiotoxicity effects of radiation have been observed 15–30 years after completion of therapy.⁹³ The location of exposure has also been reported to affect cardiotoxicity. For example, studies show that radiation over the left side of the chest, compared with the right, results in increased occurrence of cardiovascular pathology.⁹⁴ In addition, radiation exposure of the mediastinum and neck causes higher rates of cerebrovascular disease and hypertension, which could be mediated by carotid baroreceptor damage.^95,96 Known mechanisms of cardiotoxicity from radiation exposure comprise fibrosis, endothelial cell damage,²⁰ and oxidative stress.⁴⁸

Antiangiogenesis

Angiogenesis refers to the formation of new blood vessels, which can contribute to tumor growth and survival.^97,98 There are two classes of antiangiogenesis therapies for the use of cancer therapeutics: (1) antibodies specific for VEGF (e.g. bevacizumab) and (2) small molecular tyrosine kinase inhibitors (TKI) against the VEGF receptor (e.g. sorafenib and sunitinib). Although VEGF contributes to the development of cancer via the formation of new blood vessels in tumors, it also has an important role in the normal physiologic function of endothelial and renal cell survival, vasodilation, and cardiac contractile function.⁹⁹ Therefore, its inhibition has significant cardiovascular side effects. Specifically, VEGF inhibition induces conditions such as hypertension, thromboembolism, ischemia, cardiac contractile dysfunction, and heart failure.⁷⁸ A retrospective analysis of clinical trials demonstrated elevated blood pressure within 4 weeks of initiating therapy with sunitinib.⁸¹ Mechanisms that contribute to these pathophysiological states include, inhibition of nitric oxide (NO) and prostacyclin, increased production of endothelin-1,⁷⁹ oxidative stress, and cell apoptosis.⁸⁰ It is important to note that the approval for the use of bevacizumab was revoked in 2014 for the treatment of breast cancer due to high incidence of heart failure.⁷⁵ Interestingly, VEGF tyrosine kinase inhibition has an increased rate of cardiovascular toxicity, when compared with VEGF immunotherapy due to poor selectivity of the drugs and off-target effects.¹⁰⁰

Tyrosine kinase inhibitors

Due to the ubiquitous nature of tyrosine kinase receptors, the class of TKI targets several different pathways. For example, sunitinib and sorafenib target VEGF, lapatinib targets epidermal growth factor receptor (EGFR) and HER2 (see below), and imatinib targets Bcr-Abl tyrosine kinase. Inhibition of each of these tyrosine kinase receptors exerts a unique cardiovascular pathology that includes heart failure,^76,101,102 cardiomyopathy,^73,74 hypertension,⁷⁸ thromboembolism, and cardiac contractile dysfunction. In addition to mechanisms of VEGF inhibition-induced cardiovascular disease (see above), TKIs against VEGF have also been shown to disrupt mitochondrial metabolism, impair myocardial function, and result in myocardial apoptosis.⁸¹ These cardiovascular toxicity events have been shown to persist for years after therapy cessation.¹⁰³

Human epidermal growth factor receptor type 2 immunotherapy

The use of monoclonal antibodies such as trastuzumab requires routine monitoring for cardiac function. Trastuzumab is targeted against HER2, a tyrosine kinase receptor that mediates cell growth and survival. This type of cancer therapy has been shown to induce cardiac contractile dysfunction, reduction in left ventricular function, heart failure, hypertension, and increased sympathetic tone.^{49,57,85–88} Inhibition of HER2 via trastuzumab is associated with the development of cardiotoxicity as early as 4–8 weeks after initiation of therapy, albeit reversible through treatment cessation.^104,105 The cardiac myocyte HER2 receptor is activated when bound with neuregulin 1-β resulting in the promotion of protein synthesis, cell survival, and hypertrophy.¹⁰⁶ The mechanisms of cardiotoxicity are hypothesized to occur through (1) disruption of cardiac repair and myocyte homeostasis and (2) increased sympathetic tone and activation of cardiac β-adrenergic receptors.¹⁰⁷

Chemotherapeutics

Despite efficacy at reducing cancer, the use of anthracyclines is restricted by cardiotoxicity. Anthracyclines are a class of antibiotics that inhibit topoisomerase activity by intercalating between DNA base pairs, leading to DNA damage and eventual apoptosis.¹⁰⁸ Cardiotoxicity occurs both after cumulative short- and long-term anthracycline exposure causing cardiac myocyte and endothelial cell injury.^109–112 In a retrospective study of cancer patients treated with anthracyclines, the development of cardiotoxicity was positively correlated with patient age, treatment frequency, and dosage.⁵⁹ Low dose, standard-therapy breast cancer treatment with anthracyclines resulted in up to 20% of patients developing cardiac systolic dysfunction within 6 months of treatment.¹¹³ Symptoms of cardiotoxicity associated with anthracycline use include cardiomyopathy, arrhythmia, acute myocarditis,⁵⁷ heart failure,⁵⁸ left ventricular dysfunction,⁵⁹ and cardiac ischemia.^60,61 Identified mechanisms that underlie anthracycline-induced cardiotoxicity include: (1) oxidative damage to cardiac myocytes accompanied by lipid peroxidation and mitochondrial dysfunction, (2) modulation of topoisomerase activity and DNA damage, (3) alterations in multidrug-resistant efflux proteins, and (4) decreased mesenchymal and circulating progenitor cells.^{62,112,114–116}

Alkylating agents target rapidly growing cells for cell death by adding alkyl groups to DNA, thereby cross-linking the strands, resulting in the prevention of replication. As a consequence of off-target effects, this class of therapeutics also induces significant cardiotoxicity. Patients undergoing platinum-based drug treatments have been reported to develop hypertension, myocardial ischemia, thromboembolism, cerebrovascular disease, endothelial dysfunction, and coronary artery disease.^18,117 Furthermore, patients treated with agents such as cyclophosphamide and ifosfamide have been observed to develop heart failure, reduction in left ventricular function, and arrhythmias.^118,119 Nonetheless, precise mechanisms of cardiovascular toxicity are less clear. Studies have reported increased levels of intracellular adhesion molecule-1 (ICAM-1) and plasminogen activator and inhibitor type 1,^53,120 as well as exacerbated oxidative stress-induced cardiac cell death.⁵¹ However, it has been shown that cisplatin is not completely excreted from the body and patients that exhibit late vascular toxicity also have measurable platinum serum levels years after completion of therapy, which could contribute to toxicity.¹²¹

Microtubule inhibitors target and disrupt microtubule structure and function, preventing cell separation during cell division, thereby inducing cell death. Microtubules not only assist with separation during cell division, they also pro-vide cytoplasmic structure. Microtubules exist dynamically between a monomeric and polymeric form through a constant state of polymerization and depolymerization. Paclitaxel is a microtubule inhibitor, which binds to tubulin and inhibits depolymerization. Patients undergoing treatment with paclitaxel have shown increased rates of arrhythmias,⁷⁰ myocardial ischemia,⁶⁹ and coronary spasm.⁴⁹ The mechanism underlying this cardiovascular toxicity is largely unknown; however, paclitaxel has been shown to modulate calcium handling in cardiac myocytes. A study by Paul et al. (2000) demonstrated that depolymerization of microtubules increased calcium levels within the cytoplasm. There are also studies showing that disruption of the microtubule network affects cellular contraction. Chitaley and Webb (2002) demonstrated that enhanced microtubule depolymerization enhances aorta contraction in a Rho-kinase dependent manner.¹²² Nonetheless, the clinical implication of increased vascular contraction and whether it contributes to cardiovascular dysfunction in cancer survivors remains to be determined.

Antimetabolites have an increased incidence of cardiotoxicity that can occur early in cancer treatment and are proportional with dose and frequency.¹²³ Antimetabolites interfere with mitosis by substituting metabolites necessary for DNA or RNA synthesis, thus damaging cells. Common cardiovascular side effects include cardiac ischemia,^54,55 angina, disruption of cardiac electrical activity, and thrombosis.⁸⁶ The underlying mechanism of these deleterious phenotypes has been proposed to be oxidative stress and endothelial cell damage.⁵⁶

In summary, cancer therapy undoubtedly contributes to cardiovascular disease pathogenesis. There are multiple hypothesized mechanisms that have been postulated to result in cardiovascular toxicity; however, these mechanisms are broad and could be a deleterious side effect of cancer treatment, as opposed to the cause. We would like to offer an alternative hypothesis whereby cancer therapy induces cardiovascular toxicity through the action of DAMPs.

Damage-associated molecular patterns and cancer

Chronic inflammation is a distinct feature of both cardiovascular disease and cancer.⁹ However, the precise mechanisms that mediate this inflammation are only beginning to emerge. While infection is unequivocally linked to the pathogenesis of both cardiovascular disease¹²⁴ and cancer,¹²⁵ many patients with these diseases present sterile inflammation, or immune system activation in the absence of a pathogen. Although sterile inflammation has been proposed to arise through different mechanisms,¹²⁶ DAMPs and the danger theory of immunity have led to a paradigm shift in the understanding of not only pathophysiology, but physiology also.^10,11

DAMPs are endogenous molecules that have specific functional purposes inside cells and as such, are normally compartmentalized within membranes for performance of their various tasks. However, when these endogenous molecules are exposed to the extracellular environment, either by passive diffusion after membrane rupture or active secretion during stress, they unintentionally acquire additional immunogenic properties. These functions broadly include: the presentation of danger signals to other cells in a paracrine and endocrine manner, the activation of pattern-recognition receptors (PRRs) of the innate immune system, communication to the adaptive immune system and promotion of immunological memory, and finally the facilitation of tissue repair.¹²⁷ Obviously, these functions are not all mutually exclusive and the ability of DAMPs to both promote and resolve inflammation is an evolutionarily conserved mechanism to restore immunological homeostasis. However, problems arise when the expression of DAMPs becomes excessive, chronic, and uncontrolled. We propose that disease progression ensues when the expression of DAMPs exceeds a ‘pathogenicity threshold’ (Figure 2).

Figure 2.

Hypothesized schematic of how damage-associated molecular patterns (DAMPs) contribute to the treatment and progression of cancer and cardiotoxicity. Due to the paradoxical contribution of DAMPs to cancer progression in the literature, we believe two key thresholds of DAMP expression exist. The first is the ‘anti-cancer’ threshold and this is where controlled amounts of DAMPs stimulate the immune system to mount an effective defense against the growing and potentially pathogenic tumor. This explains the benefits of immunogenic cell death (ICD) to cancer remission. The second threshold is the one of pathogenicity and this is when DAMP expression becomes so excessive and chronic that uncontrolled inflammation ensues, and this contributes to the progression of cancer, resistance to anti-cancer treatments, and cardiovascular disease.

There are a large number of endogenous molecules that could potentially become DAMPs, which is dependent on the extracellular environment. Currently, DAMPs include a number of macromolecules composed of lipids, nucleic acids, and proteins from different sources such as extracellular matrix and cellular organelles. To add further complexity, macromolecules released into the extracellular environment surrounding stressed or decaying cells could be modified in such a way that their pathogenicity is either amplified or abrogated (e.g. oxidation).¹²⁸ PRRs of the innate immune system (e.g. Toll-like receptors [TLRs]) are able to recognize distinct motifs within these macromolecules. Once these macromolecules are recognized, the innate immune system responds in a manner that is motif-specific and promotes a pro-inflammatory milieu that is needed to combat the danger (e.g. upon the recognition of viral pathogen-associated molecular patterns (PAMPs), the major defensive strategy employed by the host immune system is the activation of the interferon regulatory factors). Table 2 provides several examples of DAMPs observed to be released after cancer therapy, as well as their corresponding PRR. It should be noted that this list is by no means complete, as many other unknown molecules may fulfill the inclusion criteria of being DAMPs and PRR ligands, especially in the ever-changing tumorigenic microenvironment (e.g. neoantigens).

Table 2.

Secreted or released damage-associated molecular patterns that have been measured after various anti-cancer therapies.

DAMP	Cancer type	Treatment	Author(s)	Corresponding PRR(s)
Actin	Lung squamous cell carcinoma/adenocarcinoma	Photodynamic therapy	Tracy et al.¹²⁹	DNGR-1 (CLEC9A)
Adenosine	Hairy cell leukemia	Pentostatin (2’-deoxycoformycin)	Johnston¹³⁰	A1, A2A, A2B, A3
ATP	Bladder carcinoma	Photodynamic therapy	Garg et al.¹³¹	P₂X₇, P₂Y₂
	Colorectal carcinoma and osteosarcoma	Mitoxantrone and oxaliplatin	Michaud et al.¹³²
	Colorectal carcinoma and sarcoma	Various chemotherapeutic agents	Ghiringhelli et al.¹³³
	Fibrosarcoma	Doxorubicin	Ma et al.¹³⁴
	Cutaneous melanoma	Amino acid derivative LTX-401	Eike et al.¹³⁵
	T-cell leukemia	Ultraviolet light	Elliott et al.¹³⁶
Calreticulin	Bladder carcinoma	Photodynamic therapy	Garg et al.¹³¹	CD91, scavenger receptors (LOX-1, SREC-1, and FEEL-1/CLEVER-1)
	Bladder carcinoma	Photodynamic therapy	Garg et al.¹³⁷
	Colorectal carcinoma	Doxorubicin	Obeid et al.¹³⁸
	Colorectal carcinoma	Electrohyperthermia	Andocs et al.¹³⁹
	Colorectal carcinoma and osteosarcoma	Mitoxantrone and oxaliplatin	Michaud et al.¹³²
	Colorectal carcinoma, cutaneous melanoma, lung carcinoma, esophageal squamous cell carcinoma, and pancreatic carcinoma	Various chemotherapeutic agents	Yamamura et al.¹⁴⁰
Cytochrome c	Cutaneous melanoma	Amino acid derivative LTX-401	Eike et al.¹³⁵	Unknown
Cytochrome c	Lung squamous cell carcinoma/adenocarcinoma	Photodynamic therapy	Tracy et al.¹²⁹	Unknown
HSP60	Squamous cell carcinoma	Photodynamic therapy	Korbelik et al.¹⁴¹	CD91, scavenger receptors (LOX-1, SREC-1, & FEEL-1/CLEVER-1), TLR2, TLR4
HSP70	Bladder carcinoma	Photodynamic therapy	Garg et al.¹³⁷
	Colorectal carcinoma	Oxaliplatin and 5-fluorouracil	Fang et al.¹⁴²
	Colorectal carcinoma	Electrohyperthermia	Ma et al.¹³⁴
	Lung squamous cell carcinoma/adenocarcinoma	Photodynamic therapy	Tracy et al.¹²⁹
	Prostate adenocarcinoma	Heating and UVC irradiation	Brusa et al.¹⁴³
	Squamous cell carcinoma	Photodynamic therapy	Korbelik et al.¹⁴¹
HSP90	Colorectal carcinoma	Electrohyperthermia	Ma et al.¹³⁴
	Lung squamous cell carcinoma/adenocarcinoma	Photodynamic therapy	Tracy et al.¹²⁹
	Myeloma cells	Bortezomib	Spisek et al.¹⁴⁴
GRP78 (BiP)	Squamous cell carcinoma	Photodynamic therapy	Korbelik et al.¹⁴¹
GP96 (GRP94)	Squamous cell carcinoma	Photodynamic therapy	Korbelik et al.¹⁴¹
HMGB1	Colorectal carcinoma	Doxorubicin and linoleic acid	Luo et al.¹⁴⁵	RAGE. TIM3, TLR2, TLR4, TLR9
	Colorectal carcinoma	Electrohyperthermia	Ma et al.¹³⁴
	Colorectal carcinoma	Oxaliplatin and 5-fluorouracil	Fang et al.¹⁴²
	Colorectal carcinoma and osteosarcoma	Mitoxantrone and oxaliplatin	Michaud et al.¹³²
	Colorectal carcinoma and thymoma cells	Doxorubicin and irradiation, respectively	Apetoh et al.¹⁴⁶
	Lung squamous cell carcinoma/adenocarcinoma	Photodynamic therapy	Tracy et al.¹²⁹
	Prostate adenocarcinoma	Heating and UVC irradiation	Brusa et al.¹⁴³
	Prostate adenocarcinoma	Various chemotherapeutic agents	Zhou et al.¹⁴⁷
	Cutaneous melanoma	Amino acid derivative LTX-401	Eike et al.¹³⁵
	Thymoma cells	X-rays	Apetoh et al.¹⁴⁸
IL-1α/β	Lung squamous cell carcinoma/adenocarcinoma	Photodynamic therapy	Tracy et al.¹²⁹	IL-1R
Peroxiredoxin-1	Lung squamous cell carcinoma/adenocarcinoma	Photodynamic therapy	Tracy et al.¹²⁹	CD14, TLR4
S100A8/A9	Prostate adenocarcinoma	Phorbol 12-myristate,13-acetate	Hermani et al.¹⁴⁹	RAGE
Uric acid	Thymoma cells	Etoposide and cyclophosphamide	Hu et al.¹⁵⁰	CD14, TLR2, TLR4

ATP, adenosine triphosphate; BiP, binding immunoglobulin protein; CD, cluster of differentiation; DAMP, damage-associated molecular pattern; FEEL-1/CLEVER-1, Fasciclin EGF-like/common lymphatic endothelial and vascular endothelial receptor-1; GP96, glycoprotein 96; GRP, glucose-regulated protein; HMGB1, high mobility group box 1; HSP, heat shock protein; IFN, interferon; IL, interleukin; IL-1R, interleukin-1 receptor; LOX-1, lectin-type oxidized LDL receptor 1; PRR, pattern-recognition receptor; P₂X₇, purinergic receptor P2X, ligand-gated ion channel 7; P₂Y₂, purinergic receptor P2Y, G-protein coupled 2; RAGE, receptor for advanced glycation end products; SREC-1, scavenger receptor class F member 1; TIM3, T cell/transmembrane, immunoglobulin, and mucin; TLR, Toll-like receptor; UVC, ultraviolet C.

The participation of DAMPs as the mediators of the inflammation in most cases presumes that cell death is the initiating mechanism of their release.¹⁵¹ However, determining whether cell death primarily drives pathophysiology or is a secondary bystander is difficult. Although there are many forms of cell death,¹⁵² necrosis was originally thought of as the primary source of pro-inflammatory DAMPs due to disintegration of the plasma membrane and passive release of intracellular constituents into the extracellular environment.¹⁵³ However, we have come to learn that apoptosis can also be immunostimulatory, as a result of the programed release of immunogenic molecules,^127,154 and necroptosis further refines the ability of cells to rapidly present DAMPs to the immune system with the regulated and controlled breakdown of the plasma membrane.¹⁵⁵ Cell stress or injury can also fuel the secretion of DAMPs¹²⁷ and this emphasizes that cell death is not an absolute precursor to participation of DAMPs in pathophysiology.

The participation of DAMPs in cancer is seemingly contradictory. On one hand, DAMPs have been proposed to play a beneficial role in cancer therapy by interacting with the immune system and promoting an ‘anti-cancer vaccine effect’ (Figure 2), even in the absence of a traditional adjuvant.^156–159 On the other hand, DAMPs could contribute to the progression of cancer^160–167 and promote resistance to cancer treatments.^15,147 The former is made possible due to the ability of certain cancer therapies to induce immunogenic cell death (ICD) that is associated with the emission of DAMPs from dying cancer cells. DAMPs can then be trafficked by signaling pathways, which are instigated and regulated by a complex interplay between endoplasmic reticulum stress, reactive oxygen species, and certain metabolic/biosynthetic processes.¹⁵⁸ The ultimate response of DAMPs in cancer (i.e. antitumorigenic or protumorigenic) may depend on a number of different factors,¹⁵⁶ such as:

The histopathology of the cancer (and therefore its anatomical location).

The type of cell death modality that is triggered by ICD, and the biochemical processes activated (this, in itself, may also depend on a number of different and varying factors).

The types and abundance of immune cells present to phagocytose debris.

Finally, whether a cancer antigen is recognized or not.

In summation, the conflicting contributions of DAMPs in cancer have revealed a Janus face.^157,159 Nonetheless, given the well-documented role of DAMPs in exacerbating inflammation in cardiovascular disease,¹⁶⁸ we believe that DAMPs, irrespective of their contribution to cancer treatment and progression, could serve as a novel facilitator of cardiotoxicity during and following cancer therapy.⁴⁹ DAMPs in cancer could arise from a number of different sources, including (paradoxically) tumor growth and remodeling,^160–167 as well as carcinogenic environmental toxins.¹⁶⁹

Damage-associated molecular patterns and cardiovascular disease

While it has been reviewed in more depth elsewhere,¹⁶⁸ there is ample evidence that increased levels of DAMPs are associated with cardio-vascular disease in human populations. For example, hypertensive patients have higher plasma levels of mitochondrial DNA, high mobility group box 1 (HMGB1), heat shock protein (HSP) 60 and HSP70, or fibrinogen, and each of these is capable of activating distinct PRRs that then start the immune-response cascade.¹⁶⁸ Additionally, DAMPs such as HMGB1, advanced glycation end products (AGEs), hyaluronan, oxidized low-density lipoprotein, and uric acid are present in higher levels in the circulation or the plaques in patients with atherosclerosis and S100 proteins are increased in stroke.^170,171 Consequently, PRRs such as TLRs seem to be chronically activated in cardiovascular disease, including atherosclerosis, cardiomyopathy, hypertension and cerebrovascular disease.^{12,168,172–175}

There are also strong indications from basic science studies that release of DAMPs is causative for cardiovascular disease. Thus, experimental administration of DAMPs has detrimental effects on cardiovascular parameters and inhibition of DAMPs, or their respective PRRs, improves cardiovascular disease phenotypes and outcomes.¹⁶⁸ HMGB1 administration increased myocardial infarct size and promoted the development of microvascular thrombosis.¹⁷⁶ Our group demonstrated that mitochondrial DNA infusion leads to hypertension in a pre-eclampsia rodent model.¹⁷⁷

Additionally, treatment with TLR4 or TLR9 inhibitors decreased blood pressure in spontaneous hypertensive rat (SHR), and treatment with the TLR4 inhibitor eritoran decreased myocardial ischemia-reperfusion injury;¹² TLR4 and TLR2 deficient mice are protected from doxorubicin-induced cardiomyopathy.^178,179 Genetic deficiency in various TLRs or their common downstream signaling partner MyD88 protects apolipoprotein E (apoE) knock-out mice from atherosclerosis.¹⁸⁰

Hypothesis

As discussed above, there is a clear link between cancer therapy and cardiovascular disease. While it is logical to surmise that the traditional cardiovascular disease risk factors (e.g. obesity, dyslipidemia, insulin resistance, and tobacco use) contribute to cancer therapy-induced cardiotoxicity (especially given that these are also risk factors to cancer itself), correlational analysis does not support this notion.^4,5 Therefore, the clinical and basic science data summarized in this review strongly support the notion that cancer therapy directly causes cardiovascular toxicity that would not have occurred in its absence. The mechanisms by which specific cancer therapies or radiotherapy lead to cardiovascular disease is in some cases clearly demonstrated, for instance interference with endothelial NO signaling in the case of VEGF receptor inhibitors. In the majority of remaining cases, however, the processes by which cancer therapy causes cardiovascular disease are unclear. We believe that DAMPs and innate immune-system activation are the missing contributing factors for the development of cancer therapy-induced cardiotoxicity (Figure 3).

Figure 3.

Danger signaling in cardio-oncology. The nature of cancer therapy is to reduce tumor size by causing sudden and rapid cancer-cell death. Because damage-associated molecular patterns (DAMPs) are released from dead and dying cells (via necrosis or apoptosis), this results in the release of DAMPs from cells during cancer therapy. DAMPs activate the immune system through activation of pattern-recognition receptors from cell types within the cardiovascular system (e.g. endothelial cells, vascular smooth muscle); we hypothesize that the overactivation of this system results in a pro-inflammatory cardiovascular disease following cancer therapy.

In support of this hypothesis, chemotherapeutic agents and radiotherapy are effective against cancer because they induce cell death in rapidly dividing cell populations. As a consequence of sudden cell death in a large number of cells simultaneously, there is a rapid and massive release of various DAMPs that enter the systemic circulation and induce an inflammatory response through activation of the innate immune system. As discussed above, both in vivo and in vitro treatments with chemotherapeutic agents or radiation induce release of DAMPs (Table 2). An increase in circulating DAMPs post-chemotherapy could contribute to the increased prevalence of thrombosis in cancer patients.¹⁸¹ Thrombosis has a physiological role in immune defense, where monocytes respond to PAMPs and DAMPs by releasing tissue factor and initiating coagulation pathways.¹⁸² Therefore, an increased presence of circulating DAMPs could play a role in the increased presence of thrombotic events in these patients. It has also been shown that chemo- and radio-therapy causes activation of innate immune receptors, such as PRRs.¹⁴⁶

In a perfect illustration of the Janus face effect, DAMP release and PRR activation following administration of chemotherapy may be simultaneously beneficial for cancer treatment and detrimental for other systems and organs, including the cardiovascular system. Thus, ICD can drive both immune-mediated tumor suppression and pro-inflammatory cytokine-mediated tissue injury via DAMPs. Similarly, immune cells, and in particular, T cells, also present a paradox in the context of the pathophysiology of cardio-oncology. While promoting T-cell expansion may be beneficial in diminishing cancer progression and tumorigenesis, they are also known to promote cardiovascular disease,¹⁸³ and specifically, hypertension and its associated hallmarks.¹⁸⁴

The therapeutic potential of adding agonists for TLR9 (CpG DNA), TLR3 (poly I:C), or TLR4 (endotoxin analogs) for a synergistic effect to radiotherapy or chemotherapeutics was recently evaluated and clear anti-tumor effects have been ascribed to this approach.¹⁸⁵ On the other hand, long-term consequences of TLR ligand administration on any cardiovascular parameters are only beginning to be investigated.¹⁸⁶ Data from our group and others would suggest that high amounts of DAMPs, whether released from tumor cell death following cancer therapy or administered therapeutically, might have a negative impact on the cardiovascular system.

Potential value of damage-associated molecular patterns in cardio-oncology

There are continuing advances in cancer therapeutics; however, the challenge now exists of developing avenues allowing these treatments to be efficacious without significant cost. The prevalence of cancer therapy-induced cardiotoxicity has led to systematic monitoring and the need for early identification of biomarkers for high-risk patients.^187,188 Currently, circulating cardiac troponins (TnI, TnT) are considered the gold-standard marker for cardiac injury and are used as a diagnostic adjuvant to echocardiograms and other diagnostic modalities. TnI is sensitive and specific for myocardial injury allowing for early myocardial damage detection prior to any clinical detection through physical examination or imaging, especially in anthracycline-based chemotherapy regimens.¹⁸⁹ Other studies have also looked at the usefulness of TnI and TnT as surrogate markers for myocardial damage with the use of anti-VEGF TKI chemotherapeutics.^18,190,191 Nonetheless, cardiac troponins may not be the only molecules released during cardiovascular damage after an insult such as chemotherapy or radiation. Theoretically, a wide array of circulating DAMPs could be measured in cancer patients prior to, during, and after treatment. Therefore, DAMPs present an opportunity for identifying and treating cancer therapy-induced cardiotoxicity. For example, obvious therapeutic targets for DAMPs include antagonism of the PRR activated by a specific DAMP, or direct ligand neutralization, thereby reducing the inflammation that promotes cardiovascular disease. Given the beneficial effects of DAMPs in some cancers, perhaps specific PRR antagonism in cardiovascular tissues is warranted.^156–159

In conclusion, the use of DAMPs as a diagnostic adjuvant (i.e. biomarker) or therapeutic drug could be a novel approach to decrease cardiovascular morbidity and prevent premature mortality from cardiovascular toxicity for the millions of patients that have successfully outlived their initial cancer diagnosis. After all, what is the point of tolerating the toxicity of cancer-therapy to survive cancer if you subsequently succumb to cardiovascular disease?

Footnotes

Acknowledgements

Special thanks to Theodora Szasz for her contributions to the outline and hypothesis section of the paper.

Funding

This work was supported by the National Institutes of Health (grant number HL-134604, Program Project Grant 2017-22).

Conflict of interest statement

The authors declare that there is no conflict of interest.

References

American Cancer Society. Cancer treatment and survivorship: facts and figures 2016-2017. Atlanta 2016, https://www.cancer.gov/publications/dictionaries/cancer-terms?CdrID=44004.

Wickramasinghe

Nguyen

Watson

et al . Concepts in cardio-oncology: definitions, mechanisms, diagnosis and treatment strategies of cancer therapy-induced cardiotoxicity. Future Oncol 2016; 12: 855–870.

Okwuosa

Anzevino

Rao

Cardiovascular disease in cancer survivors. Postgrad Med J 2017; 93: 82–90.

Landy

Miller

Lopez-Mitnik

et al . Aggregating traditional cardiovascular disease risk factors to assess the cardiometabolic health of childhood cancer survivors: an analysis from the Cardiac Risk Factors in Childhood Cancer Survivors Study. Am Heart J 2012; 163: 295–301.e2.

Mulrooney

Armstrong

Huang

et al . Cardiac outcomes in adult survivors of childhood cancer exposed to cardiotoxic therapy: a cross-sectional study. Ann Intern Med 2016; 164: 93–101.

Sprague

Khalil

RA.

Inflammatory cytokines in vascular dysfunction and vascular disease. Biochem Pharmacol 2009; 78: 539–552.

Granger

JP.

An emerging role for inflammatory cytokines in hypertension. Am J Physiol Heart Circ Physiol 2006; 290: H923–H924.

Dzielak

DJ.

The immune system and hypertension. Hypertension 1992; 19(Suppl. 1): I36–I44.

Koene

Prizment

Blaes

et al . Shared risk factors in cardiovascular disease and cancer. Circulation 2016; 133: 1104–1114.

10.

Matzinger

Tolerance, danger, and the extended family. Annu Rev Immunol 1994; 12: 991–1045.

11.

Matzinger

The danger model: a renewed sense of self. Science 2002; 296: 301–305.

12.

McCarthy

Wenceslau

Goulopoulou

et al . Circulating mitochondrial DNA and toll-like receptor 9 are associated with vascular dysfunction in spontaneously hypertensive rats. Cardiovasc Res 2015; 107: 119–130.

13.

McCarthy

Webb

RC.

The toll of the gridiron: damage-associated molecular patterns and hypertension in American football. FASEB J 2016; 30: 34–40.

14.

Han

Liao

Gao

et al . cTnI exacerbates myocardial ischemia/reperfusion injury by inducing adhesion of monocytes to VECs via TLR4/NF-kappaB-dependent pathway. Clin Sci 2016; 130: 2279–2293.

15.

Liu

Yang

Kang

et al . DAMP-mediated autophagy contributes to drug resistance. Autophagy 2011; 7: 112–114.

16.

Berardi

Caramanti

Savini

et al . State of the art for cardiotoxicity due to chemotherapy and to targeted therapies: a literature review. Crit Rev Oncol Hematol 2013; 88: 75–86.

17.

Bonita

Pradhan

Cardiovascular toxicities of cancer chemotherapy. Semin Oncol 2013; 40: 156–167.

18.

Cameron

Touyz

Lang

NN.

Vascular complications of cancer chemotherapy. Can J Cardiol 2016; 32: 852–862.

19.

Adams

Hardenbergh

Constine

et al . Radiation-associated cardiovascular disease. Crit Rev Oncol Hematol 2003; 45: 55–75.

20.

Taunk

Haffty

Kostis

et al . Radiation-induced heart disease: pathologic abnormalities and putative mechanisms. Front Oncol 2015; 5: 39.

21.

Weintraub

Jones

Manka

Understanding radiation-induced vascular disease. J Am Coll Cardiol 2010; 55: 1237–1239.

22.

Kaiser

When less is more: some cancer therapies may work better if doses are timed to thwart tumor evolution. Science 2017; 355: 1144–1146.

23.

Gopal

Miller

Jaffe

IZ.

Molecular mechanisms for vascular complications of targeted cancer therapies. Clin Sci 2016; 130: 1763–1779.

24.

Salami

Crews

CM.

Waste disposal – an attractive strategy for cancer therapy. Science 2017; 355: 1163–1167.

25.

Farkona

Diamandis

Blasutig

IM.

Cancer immunotherapy: the beginning of the end of cancer?

BMC Med 2016; 14: 73.

26.

National Cancer Institute. Cancer treatment: side effects. National Cancer Institute: National Institues of Health, 2015.

27.

National Cancer Institute. NCI dictionary of cancer terms: definition of cardiotoxocity, 2015, https://www.cancer.gov/publications/dictionaries/cancer-terms?CdrID=44004

28.

Bloom

Hamo

Cardinale

et al . Cancer therapy-related cardiac dysfunction and heart failure: part 1: definitions, pathophysiology, risk factors, and imaging. Circ Heart Fail 2016; 9(1): e002661.

29.

U.S. Department of Health and Human Services, National Institutes of Health, National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) v4.0, 2010.

30.

Colevas

Setser

The NCI Common Terminology Criteria for Adverse Events (CTCAE) v3.0 is the new standard for oncology trials. J Clin Oncol 2004; 22(14): 6098.

31.

US Food and Drug Administration (FDA). Doxorubicin hydrochloride liposome injection for intravenous infusion, https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/203263lbl.pdf (1995, accessed 24 March 2017).

32.

Gasowski

Piotrowicz

Breast cancer, age, and hypertension: a complex issue. Hypertension 2012; 59: 186–188.

33.

Hooning

Botma

Aleman

et al . Long-term risk of cardiovascular disease in 10-year survivors of breast cancer. J Natl Cancer Inst 2007; 99: 365–375.

34.

Dores

Abecasis

Correia

et al . Detection of early sub-clinical trastuzumab-induced cardiotoxicity in breast cancer patients. Arq Bras Cardiol 2013; 100: 328–332.

35.

Plana

Galderisi

Barac

et al . Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy: a report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr 2014; 27: 911–939.

36.

Daher

Daigle

Bhatia

et al . The prevention of cardiovascular disease in cancer survivors. Tex Heart Inst J 2012; 39: 190–198.

37.

Adams

Lipshultz

SE.

Pathophysiology of anthracycline- and radiation-associated cardiomyopathies: implications for screening and prevention. Pediatr Blood Cancer 2005; 44: 600–606.

38.

Carver

Shapiro

et al . American Society of Clinical Oncology clinical evidence review on the ongoing care of adult cancer survivors: cardiac and pulmonary late effects. J Clin Oncol 2007; 25: 3991–4008.

39.

Lenneman

Sawyer

DB.

Cardio-oncology: an update on cardiotoxicity of cancer-related treatment. Circ Res 2016; 118: 1008–1020.

40.

Hunt

SA.

ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2006; 47: 1503–1505.

41.

Kalam

Marwick

TH.

Role of cardioprotective therapy for prevention of cardiotoxicity. Eur J Cancer 2013; 49: 2900–2909.

42.

Swain

Whaley

Gerber

et al . Cardioprotection with dexrazoxane for doxorubicin-containing therapy in advanced breast cancer. J Clin Oncol 1997; 15: 1318–1332.

43.

Seicean

Plana

et al . Effect of statin therapy on the risk for incident heart failure in patients with breast cancer receiving anthracycline chemotherapy: an observational clinical cohort study. J Am Coll Cardiol 2012; 60: 2384–2390.

44.

Desai

Martin

Blumenthal

RS.

Non-cardiovascular effects associated with statins. BMJ 2014; 349: g3743.

45.

Centers for Disease Control and Prevention NCfHS. Underlying Cause of Death 1999-2013 on CDC WONDER Online Database: Centers for Disease Control and Prevention, National Center for Health Statistics; 2015 [updated 2016]. Data are from the Multiple Cause of Death Files, 1999-2013, as compiled from data provided by the 57 vital statistics jurisdictions through the Vital Statistics Cooperative Program, http://wonder.cdc.gov/ucd-icd10.html

46.

Page

IH.

The mosaic theory of arterial hypertension—its interpretation. Perspect Biol Med 1967; 10: 325–333.

47.

Groarke

Tanguturi

Hainer

et al . Abnormal exercise response in long-term survivors of Hodgkin lymphoma treated with thoracic irradiation: evidence of cardiac autonomic dysfunction and impact on outcomes. J Am Coll Cardiol 2015; 65: 573–583.

48.

Sardaro

Petruzzelli

D’Errico

et al . Radiation-induced cardiac damage in early left breast cancer patients: risk factors, biological mechanisms, radiobiology, and dosimetric constraints. Radiother Oncol 2012; 103: 133–142.

49.

Moslehi

JJ.

Cardiovascular toxic effects of targeted cancer therapies. N Engl J Med 2016; 375: 1457–1467.

50.

Tiersten

Jacobson

et al . Cardiac toxicity observed in association with high-dose cyclophosphamide-based chemotherapy for metastatic breast cancer. Breast 2004; 13: 341–346.

51.

Mythili

Sudharsan

Sudhahar

et al . Protective effect of DL-alpha-lipoic acid on cyclophosphamide induced hyperlipidemic cardiomyopathy. Eur J Pharmacol 2006; 543: 92–96.

52.

Nagi

Al-Shabanah

Hafez

et al . Thymoquinone supplementation attenuates cyclophosphamide-induced cardiotoxicity in rats. J Biochem Mol Toxicol 2011; 25: 135–142.

53.

Nuver

De Haas

Van Zweeden

et al . Vascular damage in testicular cancer patients: a study on endothelial activation by bleomycin and cisplatin in vitro. Oncol Rep 2010; 23: 247–253.

54.

Van Cutsem

Hoff

Blum

et al . Incidence of cardiotoxicity with the oral fluoropyrimidine capecitabine is typical of that reported with 5-fluorouracil. Ann Oncol 2002; 13: 484–485.

55.

Labianca

Beretta

Clerici

et al . Cardiac toxicity of 5-fluorouracil: a study on 1083 patients. Tumori 1982; 68: 505–510.

56.

Polk

Vistisen

Vaage-Nilsen

et al . A systematic review of the pathophysiology of 5-fluorouracil-induced cardiotoxicity. BMC Pharmacol Toxicol 2014; 15: 47.

57.

Bowles

Wellman

Feigelson

et al . Risk of heart failure in breast cancer patients after anthracycline and trastuzumab treatment: a retrospective cohort study. J Natl Cancer Inst 2012; 104: 1293–1305.

58.

Swain

Whaley

Ewer

MS.

Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer 2003; 97: 2869–2879.

59.

Von Hoff

Layard

Basa

et al . Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med 1979; 91: 710–717.

60.

Schwarzer

Eber

Greinix

et al . Non-Q-wave myocardial infarction associated with bleomycin and etoposide chemotherapy. Eur Heart J 1991; 12: 748–750.

61.

Durkin

Pugh

Solomon

et al . Treatment of advanced lymphomas with bleomycin (NSC-125066). Oncology 1976; 33: 140–145.

62.

Menna

Salvatorelli

Minotti

Anthracycline degradation in cardiomyocytes: a journey to oxidative survival. Chem Res Toxicol 2010; 23: 6–10.

63.

Octavia

Tocchetti

Gabrielson

et al . Doxorubicin-induced cardiomyopathy: from molecular mechanisms to therapeutic strategies. J Mol Cell Cardiol 2012; 52: 1213–1225.

64.

Lyu

Kerrigan

Lin

et al . Topoisomerase IIbeta mediated DNA double-strand breaks: implications in doxorubicin cardiotoxicity and prevention by dexrazoxane. Cancer Res 2007; 67: 8839–8846.

65.

Zhang

Liu

Bawa-Khalfe

et al . Identification of the molecular basis of doxorubicin-induced cardiotoxicity. Nat Med 2012; 18: 1639–1642.

66.

Miya

Fujikawa

Fukushima

et al . Bradycardia induced by irinotecan: a case report. Jpn J Clin Oncol 1998; 28: 709–711.

67.

Ozkan

Bal

Gulbas

Assessment and comparison of acute cardiac toxicity during high-dose cyclophosphamide and high-dose etoposide stem cell mobilization regimens with N-terminal pro-B-type natriuretic peptide. Transfus Apher Sci 2014; 50: 46–52.

68.

Cubbon

Lyon

AR.

Cardio-oncology: concepts and practice. Indian Heart J 2016; 68(Suppl. 1): S77–S85.

69.

Subar

Muggia

FM.

Apparent myocardial ischemia associated with vinblastine administration. Cancer Treat Rep 1986; 70: 690–691.

70.

Rowinsky

Eisenhauer

Chaudhry

et al . Clinical toxicities encountered with paclitaxel (Taxol). Semin Oncol 1993; 20(4 Suppl. 3): 1–15.

71.

Howarth

Calaghan

Boyett

et al . Effect of the microtubule polymerizing agent taxol on contraction, Ca²⁺ transient and L-type Ca²⁺ current in rat ventricular myocytes. J Physiol 1999; 516: 409–419.

72.

Moslehi

Deininger

Tyrosine kinase inhibitor-associated cardiovascular toxicity in chronic myeloid leukemia. J Clin Oncol 2015; 33: 4210–4218.

73.

Duran

Makarewich

Trappanese

et al . Sorafenib cardiotoxicity increases mortality after myocardial infarction. Circ Res 2014; 114: 1700–1712.

74.

Kerkela

Grazette

Yacobi

et al . Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med 2006; 12: 908–916.

75.

Choueiri

Mayer

et al . Congestive heart failure risk in patients with breast cancer treated with bevacizumab. J Clin Oncol 2011; 29: 632–638.

76.

Ran

Zhang

et al . Imatinib-induced decompensated heart failure in an elderly patient with chronic myeloid leukemia: case report and literature review. J Geriatr Cardiol 2012; 9: 411–414.

77.

Atallah

Durand

Kantarjian

et al . Congestive heart failure is a rare event in patients receiving imatinib therapy. Blood 2007; 110: 1233–1237.

78.

Bair

Choueiri

Moslehi

Cardiovascular complications associated with novel angiogenesis inhibitors: emerging evidence and evolving perspectives. Trends Cardiovasc Med 2013; 23: 104–113.

79.

Lankhorst

Saleh

Danser

et al . Etiology of angiogenesis inhibition-related hypertension. Curr Opin Pharmacol 2015; 21: 7–13.

80.

Semeniuk-Wojtas

Lubas

Stec

et al . Influence of tyrosine kinase inhibitors on hypertension and nephrotoxicity in metastatic renal cell cancer patients. Int J Mol Sci 2016; 17: 2073.

81.

Chu

Rupnick

Kerkela

et al . Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib. Lancet 2007; 370: 2011–2019.

82.

Yeh

Bickford

CL.

Cardiovascular complications of cancer therapy: incidence, pathogenesis, diagnosis, and management. J Am Coll Cardiol 2009; 53: 2231–2247.

83.

Parker

Rautela

Hertzog

PJ.

Antitumour actions of interferons: implications for cancer therapy. Nat Rev Cancer 2016; 16: 131–144.

84.

Sonnenblick

Rosin

Cardiotoxicity of interferon. A review of 44 cases. Chest 1991; 99: 557–561.

85.

Ewer

Lippman

SM.

Type II chemotherapy-related cardiac dysfunction: time to recognize a new entity. J Clin Oncol 2005; 23: 2900–2902.

86.

Lenneman

Abdallah

Smith

et al . Sympathetic nervous system alterations with HER2+ antagonism: an early marker of cardiac dysfunction with breast cancer treatment? Ecancermedicalscience. 2014; 8: 446.

87.

Hedhli

Huang

Kalinowski

et al . Endothelium-derived neuregulin protects the heart against ischemic injury. Circulation 2011; 123: 2254–2262.

88.

Pentassuglia

Sawyer

DB.

The role of Neuregulin-1beta/ErbB signaling in the heart. Exp Cell Res 2009; 315: 627–637.

89.

Scappaticci

Skillings

Holden

et al . Arterial thromboembolic events in patients with metastatic carcinoma treated with chemotherapy and bevacizumab. J Natl Cancer Inst 2007; 99: 1232–1239.

90.

Advani

Hong

Horning

et al . Cardiac toxicity associated with bevacizumab (Avastin) in combination with CHOP chemotherapy for peripheral T cell lymphoma in ECOG 2404 trial. Leuk Lymphoma 2012; 53: 718–720.

91.

Russell

Hoving

Heeneman

et al . Novel insights into pathological changes in muscular arteries of radiotherapy patients. Radiother Oncol 2009; 92: 477–483.

92.

Fajardo

LF.

Is the pathology of radiation injury different in small vs large blood vessels?

Cardiovasc Radiat Med 1999; 1: 108–110.

93.

Jaworski

Mariani

Wheeler

et al . Cardiac complications of thoracic irradiation. J Am Coll Cardiol 2013; 61: 2319–2328.

94.

McGale

Darby

Hall

et al . Incidence of heart disease in 35,000 women treated with radiotherapy for breast cancer in Denmark and Sweden. Radiother Oncol 2011; 100: 167–175.

95.

Galper

Mauch

et al . Clinically significant cardiac disease in patients with Hodgkin lymphoma treated with mediastinal irradiation. Blood 2011; 117: 412–418.

96.

Souza

Silva

Ribeiro

et al . Hypertension in patients with cancer. Arq Bras Cardiol 2015; 104: 246–252.

97.

Folkman

What is the evidence that tumors are angiogenesis dependent?

J Natl Cancer Inst 1990; 82: 4–6.

98.

Dome

Hendrix

Paku

et al . Alternative vascularization mechanisms in cancer: athology and therapeutic implications. Am J Pathol 2007; 170: 1–15.

99.

Hoeben

Landuyt

Highley

et al . Vascular endothelial growth factor and angiogenesis. Pharmacol Rev 2004; 56: 549–580.

100.

Hall

Harshman

Srinivas

et al . The frequency and severity of cardiovascular toxicity from targeted therapy in advanced renal cell carcinoma patients. JACC Heart Fail 2013; 1: 72–78.

101.

Richards

Schutz

et al . Incidence and risk of congestive heart failure in patients with renal and nonrenal cell carcinoma treated with sunitinib. J Clin Oncol 2011; 29: 3450–3456.

102.

Khakoo

Kassiotis

Tannir

et al . Heart failure associated with sunitinib malate: a multitargeted receptor tyrosine kinase inhibitor. Cancer 2008; 112: 2500–2508.

103.

Steingart

Bakris

Chen

et al . Management of cardiac toxicity in patients receiving vascular endothelial growth factor signaling pathway inhibitors. Am Heart J 2012; 163: 156–163.

104.

Hudis

CA.

Trastuzumab—mechanism of action and use in clinical practice. N Engl J Med 2007; 357: 39–51.

105.

Ewer

Vooletich

Durand

et al . Reversibility of trastuzumab-related cardiotoxicity: new insights based on clinical course and response to medical treatment. J Clin Oncol 2005; 23: 7820–7826.

106.

Khouri

Douglas

Mackey

et al . Cancer therapy-induced cardiac toxicity in early breast cancer: addressing the unresolved issues. Circulation 2012; 126: 2749–2763.

107.

Sysa-Shah

Tocchetti

Gupta

et al . Bidirectional cross-regulation between ErbB2 and beta-adrenergic signalling pathways. Cardiovasc Res 2016; 109: 358–373.

108.

Hortobagyi

GN.

Anthracyclines in the treatment of cancer. An overview. Drugs 1997; 54(Suppl. 4): 1–7.

109.

Steinherz

Tan

et al . Cardiac toxicity 4 to 20 years after completing anthracycline therapy. JAMA 1991; 266: 1672–1677.

110.

Cardinale

Colombo

Lamantia

et al . Anthracycline-induced cardiomyopathy: clinical relevance and response to pharmacologic therapy. J Am Coll Cardiol 2010; 55: 213–220.

111.

Shan

Lincoff

Young

JB.

Anthracycline-induced cardiotoxicity. Ann Intern Med 1996; 125: 47–58.

112.

Horenstein

Vander Heide

L’Ecuyer

TJ.

Molecular basis of anthracycline-induced cardiotoxicity and its prevention. Mol Genet Metab 2000; 71: 436–444.

113.

Geisberg

Abdallah

da Silva

et al . Circulating neuregulin during the transition from stage A to stage B/C heart failure in a breast cancer cohort. J Card Fail 2013; 19: 10–15.

114.

Vejpongsa

Yeh

ET.

Prevention of anthracycline-induced cardiotoxicity: challenges and opportunities. J Am Coll Cardiol 2014; 64: 938–945.

115.

McCaffrey

Tziros

Lewis

et al . Genomic profiling reveals the potential role of TCL1A and MDR1 deficiency in chemotherapy-induced cardiotoxicity. Int J Biol Sci 2013; 9: 350–360.

116.

De Angelis

Piegari

Cappetta

et al . Anthracycline cardiomyopathy is mediated by depletion of the cardiac stem cell pool and is rescued by restoration of progenitor cell function. Circulation 2010; 121: 276–292.

117.

Haugnes

Wethal

Aass

et al . Cardiovascular risk factors and morbidity in long-term survivors of testicular cancer: a 20-year follow-up study. J Clin Oncol 2010; 28: 4649–4657.

118.

Gottdiener

Appelbaum

Ferrans

et al . Cardiotoxicity associated with high-dose cyclophosphamide therapy. Arch Intern Med 1981; 141: 758–763.

119.

Quezado

Wilson

Cunnion

et al . High-dose ifosfamide is associated with severe, reversible cardiac dysfunction. Ann Intern Med 1993; 118: 31–36.

120.

Vaughn

Palmer

Carver

et al . Cardiovascular risk in long-term survivors of testicular cancer. Cancer 2008; 112: 1949–1953.

121.

Brouwers

Huitema

Beijnen

JH.

Long-term platinum retention after treatment with cisplatin and oxaliplatin. BMC Clin Pharmacol 2008; 8: 7.

122.

Chitaley

Webb

RC.

Microtubule depolymerization facilitates contraction of rat aorta via activation of Rho-kinase. Vascul Pharmacol 2002; 38: 157–161.

123.

de Forni

Malet-Martino

Jaillais

et al . Cardiotoxicity of high-dose continuous infusion fluorouracil: a prospective clinical study. J Clin Oncol 1992; 10: 1795–1801.

124.

Desvarieux

Demmer

Jacobs

Jr. et al . Periodontal bacteria and hypertension: the oral infections and vascular disease epidemiology study (INVEST). J Hypertens 2010; 28:1413–1421.

125.

Plummer

de Martel

Vignat

et al . Global burden of cancers attributable to infections in 2012: a synthetic analysis. Lancet Glob Health 2016; 4: e609–e616.

126.

Liston

Masters

SL.

Homeostasis-altering molecular processes as mechanisms of inflammasome activation. Nat Rev Immunol 2017; 17: 208–214.

127.

Venereau

Ceriotti

Bianchi

ME.

DAMPs from cell death to new life. Front Immunol 2015; 6: 422.

128.

Speer

Rohrer

Blyszczuk

et al . Abnormal high-density lipoprotein induces endothelial dysfunction via activation of Toll-like receptor-2. Immunity 2013; 18; 38: 754–768.

129.

Tracy

Bowman

Henderson

et al . Interleukin-1alpha is the major alarmin of lung epithelial cells released during photodynamic therapy to induce inflammatory mediators in fibroblasts. Br J Cancer 2012; 107: 1534–1546.

130.

Johnston

JB.

Mechanism of action of pentostatin and cladribine in hairy cell leukemia. Leuk Lymphoma 2011; 52(Suppl. 2): 43–45.

131.

Garg

Krysko

Verfaillie

et al . A novel pathway combining calreticulin exposure and ATP secretion in immunogenic cancer cell death. EMBO J 2012; 31: 1062–1079.

132.

Michaud

Martins

Sukkurwala

et al . Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice. Science 2011; 334: 1573–1577.

133.

Ghiringhelli

Apetoh

Tesniere

et al . Activation of the NLRP3 inflammasome in dendritic cells induces IL-1beta-dependent adaptive immunity against tumors. Nat Med 2009; 15: 1170–1178.

134.

Adjemian

Mattarollo

et al . Anticancer chemotherapy-induced intratumoral recruitment and differentiation of antigen-presenting cells. Immunity 2013; 38: 729–741.

135.

Eike

Mauseth

Camilio

et al . The cytolytic amphipathic beta(2,2)-amino acid LTX-401 induces DAMP release in melanoma cells and causes complete regression of B16 melanoma. PLoS One 2016; 11: e0148980.

136.

Elliott

Chekeni

Trampont

et al . Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance. Nature 2009; 461: 282–286.

137.

Garg

Krysko

Vandenabeele

et al . Hypericin-based photodynamic therapy induces surface exposure of damage-associated molecular patterns like HSP70 and calreticulin. Cancer Immunol Immunother 2012; 61: 215–221.

138.

Obeid

Tesniere

Ghiringhelli

et al . Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat Med 2007; 13: 54–61.

139.

Andocs

Meggyeshazi

Balogh

et al . Upregulation of heat shock proteins and the promotion of damage-associated molecular pattern signals in a colorectal cancer model by modulated electrohyperthermia. Cell Stress Chaperones 2015; 20: 37–46.

140.

Yamamura

Tsuchikawa

Miyauchi

et al . The key role of calreticulin in immunomodulation induced by chemotherapeutic agents. Int J Clin Oncol 2015; 20: 386–394.

141.

Korbelik

Sun

Cecic

Photodynamic therapy-induced cell surface expression and release of heat shock proteins: relevance for tumor response. Cancer Res 2005; 65: 1018–1026.

142.

Fang

Ang

et al . TLR4 is essential for dendritic cell activation and anti-tumor T-cell response enhancement by DAMPs released from chemically stressed cancer cells. Cell Mol Immunol 2014; 11: 150–159.

143.

Brusa

Migliore

Garetto

et al . Immunogenicity of 56 degrees C and UVC-treated prostate cancer is associated with release of HSP70 and HMGB1 from necrotic cells. Prostate 2009; 69: 1343–1352.

144.

Spisek

Charalambous

Mazumder

et al . Bortezomib enhances dendritic cell (DC)-mediated induction of immunity to human myeloma via exposure of cell surface heat shock protein 90 on dying tumor cells: therapeutic implications. Blood 2007; 109: 4839–4845.

145.

Luo

Chihara

Fujimoto

et al . High mobility group box 1 released from necrotic cells enhances regrowth and metastasis of cancer cells that have survived chemotherapy. Eur J Cancer 2013; 49: 741–751.

146.

Apetoh

Ghiringhelli

Tesniere

et al . The interaction between HMGB1 and TLR4 dictates the outcome of anticancer chemotherapy and radiotherapy. Immunol Rev 2007; 220: 47–59.

147.

Zhou

Chen

Gilvary

et al . HMGB1 induction of clusterin creates a chemoresistant niche in human prostate tumor cells. Sci Rep 2015; 5: 15085.

148.

Apetoh

Ghiringhelli

Tesniere

et al . Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med 2007; 13w: 1050–1059.

149.

Hermani

De Servi

Medunjanin

et al . S100A8 and S100A9 activate MAP kinase and NF-kappaB signaling pathways and trigger translocation of RAGE in human prostate cancer cells. Exp Cell Res 2006; 312 : 184–197.

150.

Moore

Thomsen

et al . Uric acid promotes tumor immune rejection. Cancer Res 2004; 64: 5059–5062.

151.

Kono

Rock

KL.

How dying cells alert the immune system to danger. Nat Rev Immunol 2008; 8: 279–289.

152.

Galluzzi

Vitale

Abrams

et al . Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012. Cell Death Differ 2012; 19: 107–120.

153.

Miyake

Yamasaki

Sensing necrotic cells. Adv Exp Med Biol 2012; 738: 144–152.

154.

Davidovich

Kearney

Martin

SJ.

Inflammatory outcomes of apoptosis, necrosis and necroptosis. Biol Chem 2014; 395: 1163–1171.

155.

Kaczmarek

Vandenabeele

Krysko

DV.

Necroptosis: the release of damage-associated molecular patterns and its physiological relevance. Immunity 2013; 38: 209–223.

156.

Garg

Martin

Golab

et al . Danger signalling during cancer cell death: origins, plasticity and regulation. Cell Death Differ 2014; 21: 26–38.

157.

Hernandez

Huebener

Schwabe

RF.

Damage-associated molecular patterns in cancer: a double-edged sword. Oncogene 2016; 35: 5931–5941.

158.

Krysko

Garg

Kaczmarek

et al . Immunogenic cell death and DAMPs in cancer therapy. Nat Rev Cancer 2012; 12: 860–875.

159.

Krysko

Love Aaes

Bachert

et al . Many faces of DAMPs in cancer therapy. Cell Death Dis 2013; 4: e631.

160.

Bettum

Vasiliauskaite

Nygaard

et al . Metastasis-associated protein S100A4 induces a network of inflammatory cytokines that activate stromal cells to acquire pro-tumorigenic properties. Cancer Lett 2014; 344: 28–39.

161.

Ghavami

Rashedi

Dattilo

et al . S100A8/A9 at low concentration promotes tumor cell growth via RAGE ligation and MAP kinase-dependent pathway. J Leukoc Biol 2008; 83: 1484–1492.

162.

Zha

Wang

et al . Tissue damage-associated “danger signals” influence T-cell responses that promote the progression of preneoplasia to cancer. Cancer Res 2013; 73: 629–639.

163.

Ichikawa

Williams

Wang

et al . S100A8/A9 activate key genes and pathways in colon tumor progression. Mol Cancer Res 2011; 9: 133–148.

164.

Jovanovic

Pejnovic

Radosavljevic

et al . Interleukin-33/ST2 axis promotes breast cancer growth and metastases by facilitating intratumoral accumulation of immunosuppressive and innate lymphoid cells. Int J Cancer 2014; 134: 1669–1682.

165.

Liu

Zhu

et al . IL-33/ST2 pathway contributes to metastasis of human colorectal cancer. Biochem Biophys Res Commun 2014; 453: 486–492.

166.

Maywald

Doerner

Pastorelli

et al . IL-33 activates tumor stroma to promote intestinal polyposis. Proc Natl Acad Sci USA 2015; 112: E2487–E2496.

167.

Sack

Walther

Scudiero

et al . Novel effect of antihelminthic niclosamide on S100A4-mediated metastatic progression in colon cancer. J Natl Cancer Inst 2011; 103: 1018–1036.

168.

McCarthy

Goulopoulou

Wenceslau

et al . Toll-like receptors and damage-associated molecular patterns: novel links between inflammation and hypertension. Am J Physiol Heart Circ Physiol 2014; 15; 306: H184–H196.

169.

Heijink

Pouwels

Leijendekker

et al . Cigarette smoke-induced damage-associated molecular pattern release from necrotic neutrophils triggers proinflammatory mediator release. Am J Respir Cell Mol Biol 2015; 52: 554–562.

170.

Foerch

Wunderlich

Dvorak

et al . Elevated serum S100B levels indicate a higher risk of hemorrhagic transformation after thrombolytic therapy in acute stroke. Stroke 2007; 38: 2491–2495.

171.

Land

WG.

The role of damage-associated molecular patterns (DAMPs) in human diseases: part II: DAMPs as diagnostics, prognostics and therapeutics in clinical medicine. Sultan Qaboos Univ Med J 2015;15(2):e157– e170.

172.

Frantz

Ertl

Bauersachs

Mechanisms of disease: toll-like receptors in cardiovascular disease. Nat Clin Pract Cardiovasc Med 2007; 4: 444–454.

173.

Montesinos

Shaw

Yee

et al . Adenosine A(2A) receptor activation promotes wound neovascularization by stimulating angiogenesis and vasculogenesis. Am J Pathol 2004; 164: 1887–1892.

174.

Lin

Chang

et al . Toll-like receptor 4 gene C119A but not Asp299Gly polymorphism is associated with ischemic stroke among ethnic Chinese in Taiwan. Atherosclerosis. 2005; 180: 305–309.

175.

Thomas

Haudek

Koroglu

et al . IRAK1 deletion disrupts cardiac Toll/IL-1 signaling and protects against contractile dysfunction. Am J Physiol Heart Circ Physiol 2003; 285: H597–H606.

176.

Ito

Kawahara

Nakamura

et al . High-mobility group box 1 protein promotes development of microvascular thrombosis in rats. J Thromb Haemost 2007; 5: 109–116.

177.

Goulopoulou

Matsumoto

Bomfim

et al . Toll-like receptor 9 activation: a novel mechanism linking placenta-derived mitochondrial DNA and vascular dysfunction in pre-eclampsia. Clin Sci 2012; 123: 429–435.

178.

Riad

Bien

Gratz

et al . Toll-like receptor-4 deficiency attenuates doxorubicin-induced cardiomyopathy in mice. Eur J Heart Fail 2008; 10: 233–243.

179.

Nozaki

Shishido

Takeishi

et al . Modulation of doxorubicin-induced cardiac dysfunction in toll-like receptor-2-knockout mice. Circulation 2004; 110: 2869–2874.

180.

Hosseini

Kanellakis

et al . Toll-like receptor (TLR)4 and MyD88 are essential for atheroprotection by peritoneal B1a B Cells. J Am Heart Assoc 2016; 5:e002947.

181.

Prandoni

Antithrombotic strategies in patients with cancer. Thromb Haemost 1997; 78: 141–144.

182.

Engelmann

Massberg

Thrombosis as an intravascular effector of innate immunity. Nat Rev Immunol 2013; 13: 34–45.

183.

Jones

True

Patel

Leukocyte trafficking in cardiovascular disease: insights from experimental models. Mediators Inflamm 2017; 2017. DOI: 10.1155/2017/9746169.

184.

Guzik

Hoch

Brown

et al . Role of the T cell in the genesis of angiotensin II induced hypertension and vascular dysfunction. J Exp Med 2007; 204: 2449–2460.

185.

Gonzalez-Reyes

Marin

Gonzalez

et al . Study of TLR3, TLR4 and TLR9 in breast carcinomas and their association with metastasis. BMC Cancer 2010; 10: 665.

186.

Goulopoulou

McCarthy

Webb

RC.

Toll-like receptors in the vascular system: sensing the dangers within. Pharmacol Rev 2016; 68: 142–167.

187.

Kilickap

Barista

Akgul

et al . cTnT can be a useful marker for early detection of anthracycline cardiotoxicity. Ann Oncol 2005; 16: 798–804.

188.

Wollert

Kempf

Wallentin

Growth differentiation factor 15 as a biomarker in cardiovascular disease. Clin Chem 2017; 63: 140–151.

189.

Cardinale

Sandri

Colombo

et al . Prognostic value of troponin I in cardiac risk stratification of cancer patients undergoing high-dose chemotherapy. Circulation 2004; 109: 2749–2754.

190.

Hurwitz

Douglas

Middleton

et al . Analysis of early hypertension and clinical outcome with bevacizumab: results from seven phase III studies. Oncologist 2013; 18: 273–280.

191.

Nakaya

Kurata

Yokoi

et al . Retrospective analysis of bevacizumab-induced hypertension and clinical outcome in patients with colorectal cancer and lung cancer. Cancer Med 2016; 5: 1381–1387.