Developing effective anticancer treatments is a particular challenge, as agents must contend with not only the target cellular biology, but also with the complex tumor microenvironment. Here we discuss various in vitro strategies that have sought to address this issue, with a particular focus on new methodologies that utilize clinical samples in basic research and their application in gene therapy and virotherapy.
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References
1.
SasieniPD, SheltonJ, Ormiston-SmithN, et al.What is the lifetime risk of developing cancer? The effect of adjusting for multiple primaries. Br J Cancer, 2011; 105:460–465.
2.
MellmanI, CoukosG, DranoffG. Cancer immunotherapy comes of age. Nature, 2012; 480:480–489.
3.
TedcastleA, CawoodR, DiY, et al.Virotherapy—cancer targeted pharmacology. Drug Discov Today, 2012; 17:215–220.
4.
HaitWN. Anticancer drug development: the grand challenges. Nat Rev Drug Discov, 2010; 9:253–254.
5.
JohnsonJI, DeckerS, ZaharevitzD, et al.Relationships between drug activity in NCI preclinical in vitro and in vivo models and early clinical trials. Br J Cancer, 2001; 84:1424–1431.
6.
SharmaSV, HaberDA, SettlemanJ. Cell line-based platforms to evaluate the therapeutic efficacy of candidate anticancer agents. Nat Rev Cancer, 2010; 10:241–253.
7.
ShoemakerRH. The NCI60 human tumour cell line anticancer drug screen. Nat Rev Cancer, 2006; 6:813–823.
8.
HolbeckSL, CollinsJM, DoroshowJH. Analysis of Food and Drug Administration-approved anticancer agents in the NCI60 panel of human tumor cell lines. Mol Cancer Ther, 2010; 9:1451–1460.
9.
AlvarezM, PaullK, MonksA, et al.Generation of a drug resistance profile by quantitation of mdr-1/P-glycoprotein in the cell lines of the National Cancer Institute Anticancer Drug Screen. J Clin Invest, 1995; 95:2205–2214.
10.
SzakácsG, AnnereauJ-P, LababidiS, et al.Predicting drug sensitivity and resistance: profiling ABC transporter genes in cancer cells. Cancer Cell, 2004; 6:129–137.
11.
FernandoA, GlaysherS, ConroyM, et al.Effect of culture conditions on the chemosensitivity of ovarian cancer cell lines. Anticancer Drugs, 2006; 17:913–919.
12.
AndreottiPE, LinderD, HartmannDM, et al.TCA-100 tumour chemosensitivity assay: differences in sensitivity between cultured tumour cell lines and clinical studies. J Biolumin Chemilumin, 1994; 9:373–378.
13.
CreeIA, GlaysherS, HarveyAL. Efficacy of anti-cancer agents in cell lines versus human primary tumour tissue. Curr Opin Pharmacol, 2010; 10:375–379.
14.
SmithJ, StewartBJ, GlaysherS, et al.The effect of pentamidine on melanoma ex vivo. Anticancer Drugs, 2010; 21:181–185.
15.
StolarekR, Gomez-ManzanoC, JiangH, et al.Robust infectivity and replication of Delta-24 adenovirus induce cell death in human medulloblastoma. Cancer Gene Ther, 2004; 11:713–720.
16.
PolJG, ZhangL, BridleBW, et al.Maraba virus as a potent oncolytic vaccine vector. Mol Ther, 2014; 22:420–429.
17.
HeidemanDAM, SteenbergenRDM, van der TorreJ, et al.Oncolytic adenovirus expressing a p53 variant resistant to degradation by HPV E6 protein exhibits potent and selective replication in cervical cancer. Mol Ther, 2005; 12:1083–1090.
18.
ValenteMJ, HenriqueR, CostaVL, et al.A rapid and simple procedure for the establishment of human normal and cancer renal primary cell cultures from surgical specimens. PLoS One, 2011; 6:e19337.
19.
KimFJ, CampagnaA, KhandrikaL, et al.Individualized medicine for renal cell carcinoma: establishment of primary cell line culture from surgical specimens. J Endourol, 2008; 22:2361–2366.
20.
HassR, BertramC. Characterization of human breast cancer epithelial cells (HBCEC) derived from long term cultured biopsies. J Exp Clin Cancer Res, 2009; 28:127.
21.
KatoS, EspinozaN, LangeS, et al.Characterization and phenotypic variation with passage number of cultured human endometrial adenocarcinoma cells. Tissue Cell, 2008; 40:95–102.
22.
DanielVC, MarchionniL, HiermanJS, et al.A primary xenograft model of small-cell lung cancer reveals irreversible changes in gene expression imposed by culture in vitro. Cancer Res, 2009; 69:3364–3373.
23.
ZouW. Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nat Rev Cancer, 2005; 5:263–274.
24.
FridmanW-H, PagèsF, Sautès-FridmanC, et al.The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer, 2012; 12:298–306.
25.
WilsonWR, HayMP. Targeting hypoxia in cancer therapy. Nat Rev Cancer, 2011; 11:393–410.
26.
RintoulRC, SethiT. Extracellular matrix regulation of drug resistance in small-cell lung cancer. Clin Sci, 2002; 102:417–424.
27.
AbbottA. Cell culture: biology's new dimension. Nature, 2003; 424:870–872.
28.
PampaloniF, ReynaudEG, StelzerEHK. The third dimension bridges the gap between cell culture and live tissue. Nat Rev Mol Cell Biol, 2007; 8:839–845.
29.
BirgersdotterA, SandbergR, ErnbergI. Gene expression perturbation in vitro—a growing case for three-dimensional (3D) culture systems. Semin Cancer Biol, 2005; 15:405–412.
30.
FriedrichJ, EbnerR, Kunz-SchughartLA. Experimental anti-tumor therapy in 3-D: spheroids—old hat or new challenge?. Int J Radiat Biol, 2007; 83:849–871.
31.
FriedrichJ, SeidelC, EbnerR, et al.Spheroid-based drug screen: considerations and practical approach. Nat Protoc, 2009; 4:309–324.
32.
HirschhaeuserF, MenneH, DittfeldC, et al.Multicellular tumor spheroids: an underestimated tool is catching up again. J Biotechnol, 2010; 148:3–15.
33.
ShenBH, HermistonTW. Effect of hypoxia on Ad5 infection, transgene expression and replication. Gene Ther, 2005; 12:902–910.
34.
ShenBH, BauzonM, HermistonTW. The effect of hypoxia on the uptake, replication and lytic potential of group B adenovirus type 3 (Ad3) and type 11p (Ad11p). Gene Ther, 2006; 13:986–990.
35.
DurandRE, OlivePL. Resistance of tumor cells to chemo- and radiotherapy modulated by the three-dimensional architecture of solid tumors and spheroids. Methods Cell Biol, 2001; 64:211–233.
36.
LamfersMLM, IdemaS, BosscherL, et al.Differential effects of combined Ad5- delta 24RGD and radiation therapy in in vitro versus in vivo models of malignant glioma. Clin Cancer Res, 2007; 13:7451–7458.
37.
MuthanaM, GiannoudisA, ScottSD, et al.Use of macrophages to target therapeutic adenovirus to human prostate tumors. Cancer Res, 2011; 71:1805–1815.
38.
GottfriedE, Kunz-SchughartLA, AndreesenR, et al.Brave little world: spheroids as an in vitro model to study tumor-immune-cell interactions. Cell Cycle, 2006; 5:691–695.
39.
GrillJ, LamfersMLM, van BeusechemVW, et al.The organotypic multicellular spheroid is a relevant three-dimensional model to study adenovirus replication and penetration in human tumors in vitro. Mol Ther, 2002; 6:609–614.
40.
GrillJ, LamfersMLM, van BeusechemVW, et al.Oncolytic virotherapy of meningiomas in vitro with replication-competent adenovirus. Neurosurgery, 2005; 56:146–153; discussion 153–154.
GraafIA, GroothuisGM, OlingaP. Precision-cut tissue slices as a tool to predict metabolism of novel drugs. Expert Opin Drug Metab Toxicol, 2007; 3:879–898.
43.
de GraafIAM, OlingaP, de JagerMH, et al.Preparation and incubation of precision-cut liver and intestinal slices for application in drug metabolism and toxicity studies. Nat Protoc, 2010; 5:1540–1551.
44.
van der KuipH, MürdterTE, SonnenbergM, et al.Short term culture of breast cancer tissues to study the activity of the anticancer drug taxol in an intact tumor environment. BMC Cancer, 2006; 6:86.
45.
VairaV, FedeleG, PyneS, et al.Preclinical model of organotypic culture for pharmacodynamic profiling of human tumors. Proc Natl Acad Sci USA, 2010; 107:8352–8356.
46.
DongM, PhilippiC, LoretzB, et al.Tissue slice model of human lung cancer to investigate telomerase inhibition by nanoparticle delivery of antisense 2′-O-methyl-RNA. Int J Pharm, 2011; 419:33–42.
47.
JoffroyCM, BuckMB, StopeMB, et al.Antiestrogens induce transforming growth factor beta-mediated immunosuppression in breast cancer. Cancer Res, 2010; 70:1314–1322.
48.
EstesJM, OliverPG, StraughnJM, et al.Efficacy of anti-death receptor 5 (DR5) antibody (TRA-8) against primary human ovarian carcinoma using a novel ex vivo tissue slice model. Gynecol Oncol, 2007; 105:291–298.
49.
DeanNR, KnowlesJA, HelmanEE, et al.Anti-EMMPRIN antibody treatment of head and neck squamous cell carcinoma in an ex-vivo model. Anticancer Drugs, 2010; 21:861–867.
50.
BeisnerJ, DongM, TaetzS, et al.Efficient telomerase inhibition in human non-small cell lung cancer cells by liposomal delivery of 2′-O-methyl-RNA. J Pharm Sci, 2009; 98:1765–1774.
51.
LiottaLA, KohnEC. The microenvironment of the tumour-host interface. Nature, 2001; 411:375–379.
52.
HwangRF, MooreT, ArumugamT, et al.Cancer-associated stromal fibroblasts promote pancreatic tumor progression. Cancer Res, 2008; 68:918–926.
53.
MiyamotoH, MurakamiT, TsuchidaK, et al.Tumor-stroma interaction of human pancreatic cancer: acquired resistance to anticancer drugs and proliferation regulation is dependent on extracellular matrix proteins. Pancreas, 2004; 28:38–44.
54.
SonnenbergM, van der KuipH, HaubeisS, et al.Highly variable response to cytotoxic chemotherapy in carcinoma-associated fibroblasts (CAFs) from lung and breast. BMC Cancer, 2008; 8:364.
55.
De PalmaM, LewisCE. Cancer: macrophages limit chemotherapy. Nature, 2011; 472:303–304.
56.
TianM, NeilJR, SchiemannWP. Transforming growth factor-β and the hallmarks of cancer. Cell Signal, 2011; 23:951–962.
57.
SalmonH, FranciszkiewiczK, DamotteD, et al.Matrix architecture defines the preferential localization and migration of T cells into the stroma of human lung tumors. J Clin Invest, 2012; 122:899–910.
58.
KernMA, HauggAM, EiteneuerE, et al.Ex vivo analysis of antineoplastic agents in precision-cut tissue slices of human origin: effects of cyclooxygenase-2 inhibition in hepatocellular carcinoma. Liver Int, 2006; 26:604–612.
59.
ThomasMA, SpencerJF, La ReginaMC, et al.Syrian hamster as a permissive immunocompetent animal model for the study of oncolytic adenovirus vectors. Cancer Res, 2006; 66:1270–1276.
60.
KirbyTO, RiveraA, ReinD, et al.A novel ex vivo model system for evaluation of conditionally replicative adenoviruses therapeutic efficacy and toxicity. Clin Cancer Res, 2004; 10:8697–8703.
61.
RotsMG, ElferinkMGL, GommansWM, et al.An ex vivo human model system to evaluate specificity of replicating and non-replicating gene therapy agents. J Gene Med, 2006; 8:35–41.
62.
Stoff-KhaliliMA, StoffA, RiveraAA, et al.Preclinical evaluation of transcriptional targeting strategies for carcinoma of the breast in a tissue slice model system. Breast Cancer Res, 2005; 7:R1141–R1152.
63.
Stoff-KhaliliMA, StoffA, RiveraAA, et al.Gene transfer to carcinoma of the breast with fiber-modified adenoviral vectors in a tissue slice model system. Cancer Biol Ther, 2005; 4:1203–1210.
64.
LiuY, LangF, XieX, et al.Efficacy of adenovirally expressed soluble TRAIL in human glioma organotypic slice culture and glioma xenografts. Cell Death Dis, 2011; 2:e121.
65.
van GeerM-A, KuhlmannKFD, BakkerCT, et al.Ex-vivo evaluation of gene therapy vectors in human pancreatic (cancer) tissue slices. World J Gastroenterol, 2009; 15:1359–1366.
66.
AlemanyR. Cancer selective adenoviruses. Mol Aspects Med, 2007; 28:42–58.
67.
ZimmermannM, ArmeanuS, SmirnowI, et al.Human precision-cut liver tumor slices as a tumor patient-individual predictive test system for oncolytic measles vaccine viruses. Int J Oncol, 2009; 34:1247–1256.
68.
van GeerM-A, BrevoordD, KuhlmannKFD, et al.A fiber modified adenovirus vector that targets to the EphrinA2 receptor reveals enhanced gene transfer to ex vivo pancreatic cancer. Int J Oncol, 2010; 36:233–244.
69.
PenningtonK, ChuQD, CurielDT, et al.The utility of a tissue slice model system to determine breast cancer infectivity by oncolytic adenoviruses. J Surg Res, 2010; 163:270–275.
70.
LiZ-Y, NiS, YangX, et al.Xenograft models for liver metastasis: relationship between tumor morphology and adenovirus vector transduction. Mol Ther, 2004; 9:650–657.
71.
BeyerI, LiZ, PerssonJ, et al.Controlled extracellular matrix degradation in breast cancer tumors improves therapy by trastuzumab. Mol Ther, 2011; 19:479–489.
72.
MühlebachMD, SchaserT, ZimmermannM, et al.Liver cancer protease activity profiles support therapeutic options with matrix metalloproteinase-activatable oncolytic measles virus. Cancer Res, 2010; 70:7620–7629.
73.
CodyJJ, DouglasJT. Armed replicating adenoviruses for cancer virotherapy. Cancer Gene Ther, 2009; 16:473–488.