Abnormal protein tyrosine kinase gene expression during melanoma progression and metastasis

Easty, David J.; Herlyn, Meenhard; Bennett, Dorothy C.

doi:10.1002/ijc.2910600119

Cited by 92 publications

(86 citation statements)

References 22 publications

(37 reference statements)

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“…On the other hand, in fibrosarcomas neither PDGF-R nor b-catenin are dephosphorylated by LMW-PTP which is conversely active on EphA2 receptor. The EphA2 receptor is overexpressed in a large number of cancers, including breast, prostate, and lung carcinomas together with melanomas and sarcomas (Easty et al, 1995;Zelinski et al, 2001;Varelias et al, 2002). In addition to its overexpression, EphA2 is functionally altered in transformed cells by regulating its tyrosine phosphorylation level.…”

Section: Discussionmentioning

confidence: 99%

LMW-PTP is a positive regulator of tumor onset and growth

et al. 2004

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Low molecular weight protein tyrosine phosphatases (LMW-PTPs) are an enzyme family that plays a key role in cell proliferation control by dephosphorylating/ inactivating both tyrosine kinase receptors (such as PDGF, insulin, and ephrin receptors) and docking proteins (such, as b-catenin) endowed with both adhesion and transcriptional activity. Besides being a frequent event in human tumors, overexpression of LMW-PTP has been recently demonstrated to be sufficient to induce neoplastic transformation. We recently demonstrated that overexpression of LMW-PTP strongly potentiates the stability of cell-cell contacts at the adherens junction level, which powerfully suggests that LMW-PTP may also contribute to cancer invasivity. Focusing on mechanisms by which LMW-PTP is involved in cancer onset and progression, the emerging picture is that LMW-PTP strongly increases fibronectin-mediated cell adhesion and mobility but, paradoxically, decreases cell proliferation. Nevertheless, LMW-PTP-transfected NIH3T3 fibroblasts engrafted in nude mice induce the onset of larger fibrosarcomas, which are endowed with higher proliferation activity as compared to mock-transfected controls. Quite opposite effects have been obtained with engrafted fibroblasts transfected with a dominant-negative form of LMW-PTP. Notably, in sarcoma extracts, LMW-PTP overexpression greatly influences the ephrin A2 (EphA2) but not PDGF receptor or b-catenin tyrosine phosphorylation. The high association of dephosphorylated EphA2 overexpression with most human cancers and our observation that cell growth stimulation by LMW-PTP overexpression is restricted to the in vivo model, strongly suggest that LMW-PTP oncogenic potential is mediated by its EphA2 tyrosine dephosphorylating activity.

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Section: Discussionmentioning

confidence: 99%

LMW-PTP is a positive regulator of tumor onset and growth

et al. 2004

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“…Indeed, many angiogenic factors are expressed by tumor cells, endothelial cells colonizing tumors, and macrophages in®ltrating the tumor (Bobik et al, 1997). Several Eph receptors are overexpressed in tumors (Hirai et al, 1987;Kiyokawa et al, 1994;Maru et al, 1988Maru et al, , 1990, particularly during the more invasive stages of tumor progression (Andres et al, 1994;Berclaz et al, 1996;Easty et al, 1995;reviewed by Dodelet and Pasquale, 2000), but in most cases their cellular distribution has not been characterized. In particular, it has been unclear whether Eph receptors and ephrins are expressed in tumor vasculature, which continuously undergoes remodeling.…”

Section: Introductionmentioning

confidence: 99%

The ephrin-A1 ligand and its receptor, EphA2, are expressed during tumor neovascularization

et al. 2000

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Eph receptor tyrosine kinases and their ephrin ligands have been implicated in embryonic vascular development and in in vivo models of angiogenesis. Eph proteins may also regulate tumor neovascularization, but this role has not been previously investigated. To screen for Eph proteins expressed in tumor blood vessels, we used tumor xenografts grown in nude mice from MDA-MB-435 human breast cancer cells or KS1767 human Kaposi's sarcoma cells. By immunohistochemistry, the ephrin-A1 ligand and one of its receptors, EphA2, were detected throughout tumor vasculature. Double-labeling with anti-CD34 antibodies demonstrated that both ephrin-A1 and EphA2 were expressed in xenograft endothelial cells and also tumor cells. Furthermore, EphA2 was tyrosinephosphorylated in the xenograft tumors, indicating that it was activated, presumably by interacting with ephrin-A1. Ephrin-A1 and EphA2 were also detected in both the vasculature and tumor cells of surgically removed human cancers. In an in vitro angiogenesis model, a dominant negative form of EphA2 inhibited capillary tube-like formation by human umbilical vein endothelial cells (HUVECs), demonstrating a requirement for EphA receptor signaling. These data suggest that ephrin-A1 and EphA2 play a role in human cancers, at least in part by in¯uencing tumor neovascularization. Eph proteins may represent promising new targets for antiangiogenic cancer treatments. Oncogene (2000) 19, 6043 ± 6052.

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“…The pigment cell mitogenic peptides identi®ed so far are FGFs (Fibroblast Growth Factors), Hepatocyte Growth Factor/Scatter Factor (HGF/SF), Mast-cell Growth Factor (MGF, known also as Kit ligand, stem-cell growth factor, and steel factor) and the neuropeptides endothelin-1, 2 and 3 (ET-1, ET-2, ET-3), (reviewed by Halaban, , 1996. The autocrine growth of melanoma cells is conferred, at least in part, by ectopic expression of growth factors (Balentien et al, 1991;Easty et al, 1995;Halaban, 1992). Of all the melanocyte growth factors listed above, bFGF (basic FGF) plays the most decisive role in the progression of normal human melanocytes to melanomas (Becker et al, 1989(Becker et al, , 1992Halaban et al, 1987Halaban et al, , 1988Halaban et al, , 1991.…”

Section: Introductionmentioning

confidence: 99%