Experimental metastasis and differentiation of murine melanoma cells: actions and interactions of factors affecting different intracellular signalling pathways

Abstract

Various factors that modulate the differentiation of malignant cells are known to affect their experimental metastatic potential (EMP), or lung colonization after intravenous injection into syngeneic animals. However, some results and conclusions on the relation between cell differentiation and metastasis have appeared to conflict. We have reanalysed this by measurement of EMP of B16 melanoma sublines after culture with agents or conditions that acted on differentiation through various intracellular pathways. All tested agents did affect the EMP. EMP was usually positively correlated with differentiation under diverse conditions, but exceptions showed that there is no direct causal connection. Nor could all findings be explained in terms of cell proliferation or expression of major histocompatibility antigens. Some data helped to explain disparities between previous reports. Specific novel findings included the following. The stimulation of EMP by melanocyte-stimulating hormone (MSH) as well as all other tested effects of MSH were prevented by extended exposure to 12-O-tetradecanoyl phorbol acetate (TPA), suggesting a requirement for protein kinase C activity as well as G-protein coupling in MSH action. Cells grown with cholera toxin were always more differentiated than untreated cells, but the EMP could be either markedly increased or markedly decreased by cholera toxin under different conditions. The basic culture medium apparently determined this striking reversal. The EMP was also significantly affected by the extracellular pH.

The antitumor properties of a nontoxic, nitric oxide–modified version of saquinavir are independent of Akt

“…Depending on the stimulus, C6 cells are able to differentiate toward both astrocytes and oligodendrocytes (18,27). B16 cells, which are derived from the same embryonic precursors as C6 cells, differentiate to acquire the characteristics of primary melanocytes when triggered by various stimuli (28)(29)(30). We found that treatment with Saq-NO prompted C6 cells to acquire some of the characteristics of oligodendrocytes.…”

Inverse relationship between invasiveness and differentiative capacity in different human neuroblastoma cell lines

“…Gabbert (1989) reported that the morphological characteristics of the tissue of origin were maintained in the inner parts of rat and human carcinomas, but lost at the invasive edges. On the other hand, Bennett et al (1994) and Prezioso et al (1993) noted a positive correlation between differentiation and metastatic potential for sub-lines of the B16 murine melanoma.…”

The role of trophic factors and autocrine/paracrine growth factors in brain metastasis

“…The second intracellular loop has two phosphorylation sites and contains consensus sequences for cAMP-dependent protein kinase recognition [133]. Stimulation of melanoma cells results in elevation of cAMP leading to melanogenesis, differentiation and growth inhibition of melanoma cells [135][136][137]. Surprisingly, treatment of murine melanoma cells with MSH can either enhance or suppress metastasis formation depending on the melanoma cells that are analyzed [136,138].…”

“…Stimulation of melanoma cells results in elevation of cAMP leading to melanogenesis, differentiation and growth inhibition of melanoma cells [135][136][137]. Surprisingly, treatment of murine melanoma cells with MSH can either enhance or suppress metastasis formation depending on the melanoma cells that are analyzed [136,138]. Melanotropins can affect not only invading melanoma cells but also the morphology and behavior of brain astroglial cells (Figure 9).…”