Vascular endothelial growth factor–A (VEGF-A) is known to play an important role in the angiogenic response essential for tumor growth in a variety of human and experimental tumors. This study was designed to investigate whether VEGF-A may play a role in the pathogenesis of recurrent respiratory papillomatosis (RRP). A retrospective study with institutional review board approval was performed at a tertiary care medical center on 12 patients with a history of laryngeal RRP. Their ages at the time of initial diagnosis ranged from 19 to 96 months (mean, 56 months). All patients had involvement of right and left true vocal cords. All patients required multiple endoscopic procedures (range, 4 to 66; mean, 12). Normal pediatric larynx samples from 5 autopsy patients were used as controls. Formalin-fixed, paraffin-embedded sections of laryngeal squamous papillomas from the 12 patients with a diagnosis of RRP and the 5 control patients were examined by in situ hybridization for the presence of messenger RNA (mRNA) for VEGF-A and vascular endothelial growth factor receptor 1 (VEGFR-1) and vascular endothelial growth factor receptor 2 (VEGFR-2). The biopsy specimens were from the true vocal cord (N = 10) or subglottis (N = 2) in the patients with RRP and consisted of large sections of larynx including the true vocal cord in the control patients (N = 5). Strong expression of VEGF-A mRNA was noted in the squamous epithelium of papillomas of all 12 patients. Strong expression of VEGFR-1 and VEGFR-2 was noted in the endothelial cells of the underlying vessels in all 12 patients. Neither strong labeling of VEGF-A mRNA nor labeling of its receptors was noted in the control patients. We conclude that the angiogenic growth factor VEGF-A is strongly expressed in the epithelium of squamous papillomas in RRP. Also, VEGFR-1 and VEGFR-2 mRNAs are strongly expressed by underlying vascular endothelial cells, suggesting an important role in the pathogenesis of RRP.
JonesSRMyersENBarnesL. Benign neoplasms of the larynx. Otolaryngol Clin North Am1984; 17: 151–78.
2.
BrownLFBerseBJackmanRW. Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in breast cancer. Hum Pathol1995; 26: 86–91.
MillauerBShawverLKPlateKHRisauWUllrichA. Glioblastoma growth inhibited in vivo by a dominant-negative Flk-1 mutant. Nature1994; 367: 576–9.
5.
BoveeJVvan den BroekLJde BoerWIHogendoornPC. Expression of growth factors and their receptors in adamantinoma of long bones and the implication for its histogenesis. J Pathol1998; 184: 24–30.
6.
BrownLFBerseBJackmanRW. Increased expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in kidney and bladder carcinomas. Am J Pathol1993; 143: 1255–62.
7.
BrownLFBerseBJackmanRW. Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in adenocarcinomas of the gastrointestinal tract. Cancer Res1993; 53: 4727–35.
8.
BrownLFTognazziKDvorakHFHarristTJ. Strong expression of kinase insert domain-containing receptor, a vascular permeability factor/vascular endothelial growth factor receptor in AIDS-associated Kaposi's sarcoma and cutaneous angiosarcoma. Am J Pathol1996; 148: 1065–74.
9.
Ffrench-ConstantCVan de WaterLDvorakHFHynesRO. Reappearance of an embryonic pattern of fibronectin splicing during wound healing in the adult rat. J Cell Biol1989; 109: 903–14.
10.
BrownLFBerseBTognazziK. Vascular permeability factor mRNA and protein expression in human kidney. Kidney Int1992; 42: 1457–61.
11.
DerkayCS. Task force on recurrent respiratory papillomas. A preliminary report. Arch Otolaryngol Head Neck Surg1995; 121: 1386–91.
12.
ArmstrongLRDerkayCSReevesWC. Initial results from the national registry for juvenile-onset recurrent respiratory papillomatosis. RRP Task Force. Arch Otolaryngol Head Neck Surg1999; 125: 743–8.
13.
SteinbergBMAubornKJ. Papillomaviruses in head and neck disease: Pathophysiology and possible regulation. J Cell Biochem Suppl1993(suppl 17F): 155–64.
14.
KoskoJRDerkayCS. Role of cesarean section in prevention of recurrent respiratory papillomatosis — is there one?Int J Pediatr Otorhinolaryngol1996; 35: 31–8.
15.
SilverbergMJThorsenPLindebergHGrantLAShahKV. Condyloma in pregnancy is strongly predictive of juvenile-onset recurrent respiratory papillomatosis. Obstet Gynecol2003; 101: 645–52.
AvidanoMASingletonGT. Adjuvant drug strategies in the treatment of recurrent respiratory papillomatosis. Otolaryngol Head Neck Surg1995; 112: 197–202.
19.
RosenCAWoodsonGEThompsonJWHengestegAPBradlowHL. Preliminary results of the use of indole-3-carbinol for recurrent respiratory papillomatosis. Otolaryngol Head Neck Surg1998; 118: 810–5.
20.
DvorakHFNagyJAFengDBrownLFDvorakAM. Vascular permeability factor/vascular endothelial growth and the significance of microvascular hyperpermeability in angiogenesis. Curr Top Microbiol Immunol1999; 237: 97–132.
21.
DvorakHFDvorakAMManseauEJWibergLChurchillWH. Fibrin gel investment associated with line 1 and line 10 solid tumor growth, angiogenesis, and fibroplasia in guinea pigs. Role of cellular immunity, myofibroblasts, microvascular damage, and infarction in line 1 tumor regression. J Natl Cancer Inst1979; 62: 1459–72.
22.
DvorakHFOrensteinNSCarvalhoAC. Induction of a fibrin-gel investment: An early event in line 10 hepatocarcinoma growth mediated by tumor-secreted products. J Immunol1979; 122: 166–74.
23.
SengerDRGalliSJDvorakAMPerruzziCAHarveyVSDvorakHF. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science1983; 219: 983–5.
24.
SengerDRPerruzziCAFederJDvorakHF. A highly conserved vascular permeability factor secreted by a variety of human and rodent tumor cell lines. Cancer Res1986; 46: 5629–32.
FerraraNHenzelWJ. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem Biophys Res Commun1989; 161: 851–8.
27.
GospodarowiczDAbrahamJASchillingJ. Isolation and characterization of a vascular endothelial cell mitogen produced by pituitary-derived folliculo stellate cells. Proc Natl Acad Sci USA1989; 86: 7311–5.
28.
KeckPJHauserSDKriviG. Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science1989; 246: 1309–12.
29.
ClaussMGerlachMGerlachH. Vascular permeability factor: A tumor-derived polypeptide that induces endothelial cell and monocyte procoagulant activity, and promotes monocyte migration. J Exp Med1990; 172: 1535–45.
30.
BrownLFGuidiAJSchnittSJ. Vascular stroma formation in carcinoma in situ, invasive carcinoma, and metastatic carcinoma of the breast. Clin Cancer Res1999; 5: 1041–56.
31.
PepperMSFerraraNOrciLMontesanoR. Vascular endothelial growth factor (VEGF) induces plasminogen activators and plasminogen activator inhibitor–1 in microvascular endothelial cells. Biochem Biophys Res Commun1991; 181: 902–6.
32.
BrownLFOlbrichtSMBerseB. Overexpression of vascular permeability factor (VPF/VEGF) and its endothelial cell receptors in delayed hypersensitivity skin reactions. J Immunol1995; 154: 2801–7.
33.
BrownLFYeoK-TBerseB. Expression of vascular permeability factor (vascular endothelial growth factor) by epidermal keratinocytes during wound healing. J Exp Med1992; 176: 1375–9.
34.
PierceEAAveryRLFoleyEDAielloLPSmithLE. Vascular endothelial growth factor/vascular permeability factor expression in a mouse model of retinal neovascularization. Proc Natl Acad Sci USA1995; 92: 905–9.
35.
FavaRAOlsenNJSpencer-GreenG. Vascular permeability factor/endothelial growth factor (VPF/VEGF): Accumulation and expression in human synovial fluids and rheumatoid synovial tissue. J Exp Med1994; 180: 341–6.
36.
DetmarMBrownLFClaffeyKP. Overexpression of vascular permeability factor/vascular endothelial growth factor and its receptors in psoriasis. J Exp Med1994; 180: 1141–6.
37.
DvorakHF. Tumors: Wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med1986; 315: 1650–9.
DvorakHFHarveyVSMcDonaghJ. Quantitation of fibrinogen influx and fibrin deposition and turnover in line 1 and line 10 guinea pig carcinomas. Cancer Res1984; 44: 3348–54.
40.
BrownLFChesterJFMaltRADvorakHF. Fibrin deposition in autochthonous Syrian hamster pancreatic adenocarcinomas induced by the chemical carcinogen N-nitroso-bis(2-oxopropyl)amine. J Natl Cancer Inst1987; 78: 979–86.
41.
SivakumarBHarryLEPaleologEM. Modulating angiogenesis: More vs less. JAMA2004; 292: 972–7.
42.
WeidnerNSempleJPWelchWRFolkmanJ. Tumor angiogenesis and metastasis — correlation in invasive breast carcinoma. N Engl J Med1991; 324: 1–8.
43.
WeidnerNFolkmanJPozzaF. Tumor angiogenesis: A new significant and independent prognostic indicator in early-stage breast carcinoma. J Natl Cancer Inst1992; 84: 1875–87.
44.
MyersRBOelschlagerDManneUCoanPNWeissHGrizzleWE. Androgenic regulation of growth factor and growth factor receptor expression in the CWR22 model of prostatic adenocarcinoma. Int J Cancer1999; 82: 424–9.
45.
De LucaACasamassimiASelvamMP. EGF-related peptides are involved in the proliferation and survival of MDA-MB-468 human breast carcinoma cells. Int J Cancer1999; 80: 589–94.
