Human Melanoma Cells Secrete and Respond to Placenta Growth Factor and Vascular Endothelial Growth Factor

Abstract

The vascular endothelial growth factor is produced by a large variety of human tumors, including melanoma, in which it appears to play an important role in the process of tumor-induced angiogenesis. Little information is available on the role of placenta growth factor, a member of the vascular endothelial growth factor family of cytokines, in tumor angiogenesis, even though placenta growth factor/vascular endothelial growth factor heterodimers have been recently isolated from tumor cells. To investigate the role of placenta growth factor and vascular endothelial growth factor homodimers and heterodimers in melanoma angiogenesis and growth, 19 human melanoma cell lines derived from primary or metastatic tumors were characterized for the expression of these cytokines and their receptors. Release of placenta growth factor and vascular endothelial growth factor polypeptides into the supernatant of human melanoma cells was demonstrated. Reverse transcriptase polymerase chain reaction analysis showed the presence of mRNAs encoding at least three different vascular endothelial growth factor isoforms (VEGF(121), VEGF(165), and VEGF(189)) and transcripts for two placenta growth factor isoforms (PlGF-1 and PlGF-2) in human melanoma cells. In addition, placenta growth factor expression in human melanoma in vivo was detected by immunohistochemical staining of tumor specimens. Both primary and metastatic melanoma cells were found to express the mRNAs encoding for vascular endothelial growth factor and placenta growth factor receptors (KDR, Flt-1, neuropilin-1, and neuropilin-2), and exposure of melanoma cells to these cytokines resulted in a specific proliferative response, supporting the hypothesis of a role of these angiogenic factors in melanoma growth. J Invest Dermatol 115:1000-1007 2000

Angiogenesis, lymphangiogenesis, and melanoma metastasis

“…Angiogenesis and melanoma M Streit and M Detmar these studies demonstrated that VEGF expression is not as prominent in melanomas as in most epithelial cancers (Dvorak et al, 1995) and, therefore, might not represent the major angiogenic activity in these tumors, the expression of functional VEGF receptors on human melanoma cells suggests the intriguing possibility that VEGF might also exert autocrine effects on the tumor cells themselves (Gitay-Goren et al, 1993;Liu et al, 1995;Graeven et al, 1999;Lacal et al, 2000). Expression of mRNA for basic fibroblast growth factor (bFGF, FGF-2), a potent angiogenesis factor, has been detected in metastatic and primary invasive melanomas, whereas melanocytes in benign nevi did not express this factor (Reed et al, 1994) .…”

“…Moreover, in a series of 125 melanoma patients, IL-8 serum levels were found to be elevated, compared to healthy controls, and were correlated with an advanced disease stage and poor progression-free and overall survival (Ugurel et al, 2001). Immunohistochemical analysis revealed increased expression levels of the angiogenic factors placental growth factor (PlGF; Lacal et al, 2000), platelet-derived growth factor (PDGF)-AA and -BB (Barnhill et al, 1996), and angiogenin (Hartmann et al, 1999) in human melanoma tissue samples. However, the prognostic value of these factors and their potential importance for melanoma metastasis remain at present unclear.…”

Role of PLZF in melanoma progression

“…The early passage melanoma cells were kindly provided by Dr S D'Atri (IDI IRCCS, Rome). Two cell lines were obtained from primary tumors (GR-mel, ST-mel) and three from lymph node metastases (CRmel, CN-mel, MR/C-mel) (Lacal PM et al, 2000;Alvino et al, 2002). Normal human epidermal melanocytes from foreskin were obtained from Promocell (Heidelberg, Germany).…”

Crosstalk between peroxisome proliferator-activated receptor δ and VEGF stimulates cancer progression

“…Although the role of VEGF in stimulating tumor-associated angiogenesis through binding to VEGFRs on endothelial cells is well documented, emerging data suggest that VEGFRs are expressed in liquid and solid tumor cells including hematopoietic malignancies (21,22), non-small-cell lung carcinomas (23), prostate cancer (24), melanoma (25), and breast cancer (26). These findings imply a potential role for the VEGF/VEGFR autocrine loop in cancer biology.…”