We demonstrate here that human T cells, upon activation, neo-express the melanoma metastasis-associated surface molecule MUC18/melanoma cell adhesion molecule (MCAM).
To provide direct evidence that MCAM plays a role in tumor growth and metastasis of human melanoma, the nonmetastatic MCAM-negative primary cutaneous melanoma SB-2 cells were transfected with MCAM cDNA and analyzed subsequently for changes in their tumorigenic and metastatic potential.
To our knowledge, this is the first demonstration that MUC18 is involved in cell signaling regulating the expression of Id-1 and ATF-3, thus contributing to melanoma metastasis.
To mimic physiological situations, we used pooled METCAM/MUC18-expressing and control (vector) clones for testing effects of human METCAM/MUC18 over-expression on in vitro motility and invasiveness, and on in vivo tumor formation and metastasis in female athymic nude mice.
Therefore, CD146-mediated regulation of the E-cadherin-to-N-cadherin switch provides an insight into the general mechanisms of EMT as well as cancer metastasis.
The objective of the study was to use CD146 mRNA to predict the evolution of patients with non-metastatic clear cell renal cell carcinoma (M0 ccRCC) towards metastatic disease, and to use soluble CD146 (sCD146) to anticipate relapses on reference treatments by sunitinib or bevacizumab in patients with metastatic ccRCC (M1).
The nestin-positive group of patients and the CD146-positive group of patients presented significantly higher rates of disease recurrence (log-rank test, p = 0.022 for nestin and p = 0.003 for CD146) with a distant metastasis, 30 months after the primary treatment.
The level of its expression has been found to correlate directly with tumour progression and metastatic potential, thus establishing CD146 as an important candidate of tumour growth and metastasis.
The influence of MCAM expression on lung metastases formation in an experimental metastasis assay was system dependent, converting only XP44RO(Mel) transfectants into metastatic cells, although increased homotypic adhesion, leading to formation of tumor cell clusters, was observed with transfectants of both cell lines in vitro.
The G418-resistant (G418R)-LNCaP clones that expressed a high level of huMUC18 were selected and used for testing the effect of huMUC18 expression on the in vitro growth, motility, and invasiveness as well as on the in vivo metastasis (via orthotopical injection) in a xenograft nude mouse model.
Taken together, the results suggested that CK19, CD105 and CD146 markers of peripheral blood may be considered to be effective tools to evaluate the early metastasis in a CTC-positive condition.
Specifically, we demonstrate that MCAM depletion, like KDM3A depletion, inhibits cell migration in vitro and experimental metastasis in vivo, and that MCAM partially rescues impaired migration due to KDM3A knock-down.
Since E-cadherin is a melanoma invasion suppressor, and MCAM is a melanoma invasion promoter, ET-1 may promote melanoma invasion and metastasis through the regulation of adhesion molecule expression.
S100A8/A9-MCAM binding activates mitogen-activated protein kinase kinase kinase 8 (MAP3K8), also termed TPL2, leading to strong activation of the transcription factor ETV4 and subsequent induction of matrix metalloproteinase-25 (MMP25), and finally to induction of melanoma lung tropic metastasis.
Positive CD146 expression, and average microvessel and lymph vessel counts were also significantly lower in cases with well-differentiated adenocarcinoma, maximal tumor diameter <2 cm, no metastasis of lymph node, and no invasion of regional tissues than in cases with poorly differentiated adenocarcinoma, maximal tumor diameter ≥ 2 cm, metastasis in lymph nodes, and invasion of regional tissues (p < 0.05 or p < 0.01).
Overall, our results revealed that ETV4 is a novel transcription factor regulated by the S100A8/A9-MCAM axis, which leads to EMT through ZEB1 and thereby to metastasis in breast cancer cells.
Loss of AP-2α and overexpression of CREB/ATF-1 results in the overexpression of MCAM/MUC18 which by itself contributes to melanoma metastasis by regulating the inhibitor of DNA binding-1 (Id-1).
In nonmetastatic cells, however, melanoma cell adhesion molecule expression is repressed and we speculate that stem cell factor/c-Kit signaling might be responsible for the control of melanoma cell adhesion molecule synthesis, and thus, perhaps, of melanoma progression and metastasis.
In addition, the cell-surface adhesion molecule MCAM/MUC18 that is involved in metastasis of human melanoma was downregulated in the KCREB-transfected cells.
In tumor metastasis PCR microarray, 24 genes related to cell invading, adhesion, cellular growth and differentiation were found with a twofold difference between SW1116-S5 and SW1116-M. Sixteen of these, including E-cadherins, MTSS1, TRAIL and TRPM1, were up-regulated; eight genes including cathepsin L, EphB2, HGF, MET, MCAM and RORβ were down-regulated.