In vivo Switching of Human Melanoma Cells between Proliferative and Invasive States

Abstract

Metastatic melanoma represents a complex and heterogeneous disease for which there are no therapies to improve patient survival. Recent expression profiling of melanoma cell lines identified two transcription signatures, respectively, corresponding with proliferative and invasive cellular phenotypes. A model derived from these findings predicts that in vivo melanoma cells may switch between these states. Here, DNA microarray-characterized cell lines were subjected to in vitro characterization before s.c. injection into immunocompromised mice. Tumor growth rates were measured and postexcision samples were assessed by immunohistochemistry to identify invasive and proliferative signature cells. In vitro tests showed that proliferative signature melanoma cells are faster growing but less motile than invasive signature cells. In vivo proliferative signature cells initiated tumor growth in 14 F 3 days postinjection. By comparison, invasive signature cells required a significantly longer (P < 0.001) period of 59 F 11 days. Immunohistochemistry showed that regardless of the seed cell signature, tumors showed evidence for both proliferative and invasive cell types. Furthermore, proliferative signature cell types were detected most frequently in the peripheral margin of growing tumors. These data indicate that melanoma cells undergo transcriptional signature switching in vivo likely regulated by local microenvironmental conditions. Our findings challenge previous models of melanoma progression that evoke one-way changes in gene expression. We present a new model for melanoma progression that accounts for transcription signature plasticity and provides a more rational context for explaining observed melanoma biology. [Cancer Res 2008;68(3):650-6]

Breast cancer suppressor candidate‐1 (BCSC‐1) is a melanoma tumor suppressor that down regulates MITF

“…This was also in agreement with observations that showed increased expression of MITF in MM (Gray-Schopfer et al, 2007). In addition, BCSC-1 overexpression in Mewo cells decreased MITF expression (Table S1) (low MITF levels) phenotype (Hoek et al, 2008a). Our gene expression studies in Mewo cells showed that BCSC-1 overexpression decreased MITF mRNA levels (Table S1).…”

The influence of sentinel lymph node tumour burden on additional lymph node involvement and disease-free survival in cutaneous melanoma – a retrospective analysis of 392 cases

“…Although our study confirms that predicting non-SLN positivity on the basis of SLN tumour load is unreliable, it demonstrates that SLN tumour burden has an impact on DFS. Recent experimental studies using melanoma cell lines in mice have impressively shown that melanoma cells can switch their transcriptional profile from an invasive migrating one to a proliferative profile associated with melanocytic differentiation (Hoek et al, 2008). We hypothesise that the evaluation of the invasive markers in melanoma metastases might improve the predictive accuracy of the SN status.…”

Aberrant miR-182 expression promotes melanoma metastasis by repressing FOXO3 and microphthalmia-associated transcription factor

“…[20][21][22]. However, direct measurements of MITF during melanoma progression by ourselves and others (23)(24)(25) suggest that MITF is more commonly down-regulated in advanced melanoma.…”