CD271 Down-Regulation Promotes Melanoma Progression and Invasion in Three-Dimensional Models and in Zebrafish

Abstract

CD271 is a neurotrophin receptor variably expressed in melanoma. Although contradictory data are reported on its role as a marker of tumor-initiating cells, little is known about its function in tumor progression. CD271 expression was higher in spheroids derived from freshly isolated cells of primary melanomas and in primary WM115 and WM793-B cell lines, and it decreased during progression to advanced stages in cells isolated from metastatic melanomas and in metastatic WM266-4 and 1205Lu cell lines. Moreover, CD271 was scarcely detected in the highly invasive spheroids (SKMEL28 and 1205Lu). CD271, originally expressed in the epidermis of skin reconstructs, disappeared when melanoma started to invade the dermis. SKMEL8 CD271(-) cells showed greater proliferation and invasiveness in vitro and were associated with a higher number of metastases in zebrafish compared with CD271(+) cells. CD271 silencing in WM115 induced a more aggressive phenotype in vitro and in vivo. On the contrary, CD271 overexpression in SKMEL28 cells reduced invasion in vitro, and CD271 overexpressing 1205Lu cells was associated with a lower percentage of metastases in zebrafish. A reduced cell-cell adhesion was also observed in the absence of CD271. Taken together, these results indicate that CD271 loss is critical for melanoma progression and metastasis.

p75 Neurotrophin Receptor in the Skin: Beyond Its Neurotrophic Function

“…The low levels of β 1 integrin and the decreased of cell-to-cell adhesion in the absence of p75 NTR could predispose melanoma to increased invasiveness (93). Furthermore, melanoma is characterized by an alteration of the apoptotic machinery.…”

“…To definitely assess the role of p75 NTR in melanoma, we have recently carried out an extensive study in vitro and in vivo (93). In skin equivalent models, p75 NTR is highly expressed in early melanomas at the epidermal level and tends to disappear when melanoma starts to invade the dermis.…”

Progress in melanoma modelling in vitro

“…We previously demonstrated that in melanoma MCTS, the expression level of several melanoma markers (CD271, HIF‐1α, ABCB5 and Oct4) observed in skin lesion and freshly isolated cells are maintained in spheroids derived from the same patients up to 168 hours …”

“…Figure shows an example of this assay performed using five melanoma cell lines of different origin. To quantify the invasive ability, it is possible to measure the spheroids area and the invasion area in pixel by ImageJ software, the factor shape, the percentage of fragmentation and the distance reached by cells, as reported in several studies . It should be also noted that the presence of stromal cells would better recapitulate the tumor microenvironment.…”

Cancer stem cells, stemness markers and selected drug targeting: metastatic colorectal cancer and cyclooxygenase-2/prostaglandin E2 connection to WNT as a model system

“…Moreover, OCT4 expression in melanoma cells was induced by hypoxia and its expression was detected in a sub-population of melanoma cells from clinical samples [141] . Overexpressing CD271 on human melanoma cell lines was shown to reduce their invasive and metastatic traits, whereas CD271melanoma cells showed less adhesive, more highly proliferative and invasive traits in vitro and in vivo [142] . Mechanistically, similar to EPCAM, it was found that the CD271 ICD regulated proliferation [143] .…”