P-cadherin expression reduces melanoma growth, invasion, and responsiveness to growth factors in nude mice

Abstract

The prognostic discrepancy between localized melanoma and metastatic disease demands a better understanding of melanoma progression. The role of E-cadherin and N-cadherin in melanoma has been widely studied; however, the function of P-cadherin remains to be elucidated. We wanted to assess the effects of P-cadherin overexpression in BLM melanoma cells with regard to xenograft growth, invasion, and survival of mice in our model to mimic micrometastatic spread. Swiss nu/nu mice were subcutaneously injected with control (BLM LIE) and P-cadherin overexpressing (BLM P-cad) melanoma cells alone and in combination with myofibroblasts, and intracardially injected with BLM LIE and BLM P-cad cells. Tumor volumes and survival of mice were assessed and analyzed. In-vitro assays were used to further investigate the influence, and identify the target receptors of growth factors secreted by myofibroblasts in melanoma cells. In-vivo experiments point out that P-cadherin reduces xenograft growth (1621 mm ± 107 vs. 329 mm ± 71) and invasion, and prolongs overall survival (34.1 ± 0.84 vs. 51.1 ± 1.8 days) of mice in our model to mimic micrometastatic spread. Coinjection with myofibroblasts resulted in increased tumor growth in BLM LIE (3896 mm ± 64 vs. 1621 mm ± 107) in contrast to BLM P-cad (417 mm ± 47 vs. 329 ± 71). P-cadherin reduces melanoma growth and invasion, prolongs the survival of mice intracardially injected, and induces a state of decreased responsiveness to myofibroblast-derived growth factors. Therefore, P-cadherin can be considered as a potential therapeutic target in the treatment of melanoma.

P-cadherin and the journey to cancer metastasis

“…Studies from Bracke and colleagues have shown an invasion suppressor role for E-cadherin and P-cadherin on melanoma, which decrease their membranous expression when the disease progresses to a metastatic stage [ 43 , 44 ]. De novo expression of P-cadherin in melanoma cells reduced xenograft tumour growth and prolonged mouse survival in a model mimicking micrometastatic spread [ 44 ], as well as promoted adhesive cell-cell contacts and anti-invasive effects in vitro . This response was abolished when targeted mutations on the P-cadherin intracellular juxtamembrane domain or on its extracellular domain were introduced [ 43 ].…”

P-Cadherin Regulates Human Hair Growth and Cycling via Canonical Wnt Signaling and Transforming Growth Factor-β2

“…This invites exploitation of organ-cultured human HFs and skin as attractive preclinical models for dissecting the molecular and cellular consequences of P-cadherin loss of function in situ. Availability of such an experimental model constitutes a significant methodological advance, as the functions of P-cadherin mediated signaling in human epithelial physiology are as yet ill-understood (Faraldo et al, 2007;Shimomura et al, 2008;Bandara et al, 2010;Jacobs et al, 2011).…”

Downregulation of P-cadherin expression in hepatocellular carcinoma induces tumorigenicity

“…There are contrasting studies about the role of the classical cadherin P-cadherin in human cancers pointing toward a dual role of Pcadherin as both an oncogene as well as a tumor suppressor [27,28]. In this study, we found reduced expression of P-cadherin in HCC-cell lines and tissues.…”