MCAM (CD146) is a cell surface adhesion molecule that has been reported to promote cancer development, progression and metastasis and is considered as a potential tumor biomarker and therapeutic target.
CD146 is a multifunctional molecule and is implicated in tumour invasion and metastasis; however, its role in lung cancer has not been clearly established.
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.
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.
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).
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.
Elevated MCAM expression was inversely correlated with recurrence-free and distant metastasis-free survival in a cohort of 4142 patients with breast cancer derived from a public database, particularly in the subgroup only treated with tamoxifen.
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.
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.
Different intrinsic co-factors in different K1735 sublines, which modulate the functions of MCAM/MUC18 in the cells that interact differently to the tumor microenvironment, may render sublines manifest differently in tumorigenicity and metastasis in vivo.
Cell surface glycoprotein MUC18 (alias CD146 or melanoma cell adhesion molecule) has been shown to promote metastasis in several tumors, including melanoma.
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.
An orthotopic breast tumor model demonstrated that CD146-overexpressing breast tumors showed a poorly differentiated phenotype and displayed increased tumor invasion and metastasis.
Antagonistic effects of JAM-A, a tight junction-associated protein, on CD146 promigratory effects underline the complexity of the adhesion molecules network in tumor cell migration and metastasis.
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.
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).