Platelet-derived growth factor-B normalizes micromorphology and vessel function in vascular endothelial growth factor-A-induced squamous cell carcinomas.
Vascular endothelial growth factor (VEGF), which is a key regulator of angiogenesis, often induces formation of immature vessels with increased permeability and reduced vessel functionality. Here, we demonstrate that de novo expression of murine (m)VEGF-164 induces malignant and invasive tumor growth of HaCaT keratinocytes. However, the mVEGF-164-induced tumors are ulcerated with a disorganized epithelium that is interrupted by lacunae with limited basement membrane and endothelial cell coverage. Vessel maturation is strongly impaired. Tumor and vessel micromorphology are markedly improved by the combined expression of human platelet-derived growth factor (hPDGF)-B and mVEGF-164. Although tumor size and malignancy are comparable with either mVEGF-164 alone or combined human PDGF-B and mVEGF-164 expression, combined hPDGF-B and mVEGF-164 expression leads to a more solid and compact tumor tissue with a mature functional tumor vasculature and a higher microvessel density, as demonstrated histologically and by dynamic contrast-enhanced magnetic resonance imaging. Treatment of the hPDGF-B- and mVEGF-164-expressing tumors with imatinib mesylate to block PDGF-B signaling reverses this effect. In addition, tumor cell invasion of mVEGF-164 transfectants and mVEGF-164 plus hPDGF-B transfectants in vivo is associated with a marked induction of tumor-derived matrix metalloproteinase-1 and stromal matrix metalloproteinase-9 and -13, as was confirmed in three-dimensional organotypic co-cultures with fibroblasts in vitro. These data clearly demonstrate the need for a concerted action of different growth factors in the establishment of solid tumors with functional vasculature and emphasize the need for a multifactorial therapy.
Lederle
Wiltrud
W
Tumor and Microenvironment (A101), German Cancer Research Center, INF 280, 69120 Heidelberg, Germany.
Linde
Nina
N
Heusel
Julia
J
Bzyl
Jessica
J
Woenne
Eva C
EC
Zwick
Stefan
S
Skobe
Mihaela
M
Kiessling
Fabian
F
Fusenig
Norbert E
NE
Mueller
Margareta M
MM
D000818:Animals; D001549:Benzamides; D002294:Carcinoma, Squamous Cell / Q000098:blood supply / Q000235:genetics / Q000473:pathology* / Q000648:ultrastructure; D049109:Cell Proliferation; D002478:Cells, Cultured; D006801:Humans; D000068877:Imatinib Mesylate; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis / Q000235:genetics / Q000502:physiology*; D011743:Pyrimidines / Q000494:pharmacology; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors; D012878:Skin Neoplasms / Q000098:blood supply / Q000235:genetics / Q000473:pathology* / Q000648:ultrastructure; D014162:Transfection; D014183:Transplantation, Heterologous; D047368:Tumor Burden / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*
D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D020574:Proto-Oncogene Proteins c-sis; D011743:Pyrimidines; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068877:Imatinib Mesylate; D020797:Receptor, Platelet-Derived Growth Factor beta