Malignant Melanoma and Its Stromal Nonimmune Microecosystem

Abstract

In recent years, rapid advances were reached in the understanding of a series of biologic signals influencing cutaneous malignant melanoma (CMM) cells. CMM is in close contact with a peculiar dermal extracellular matrix (ECM). Stromal cells store and release various structural ECM components. The impact on CMM growth and progression is mediated through strong and long-lasting effects of ECM products. This paper summarizes some peculiar aspects of the peri-CMM stroma showing intracytoplasmic loads in Factor XIIIa, CD34, versican, and α (IV) collagen chains. The restricted peri-CMM skin territory exhibiting such changes corresponds to the area showing neoangiogenesis and extravascular unicellular metastatic spread. The latter inconspicuous migratory CMM cells possibly correspond to CMM stem cells or to CMM cells with aberrant HOX gene expression. Their presence is associated with an increased risk for metastases in the regional sentinel lymph nodes. In conclusion, the CMM-stroma connection appears crucial to the growth regulation, invasiveness and initial metastatic spread of CMM cells. Although much remains to be learned in this field, the active intervention of the peri-CMM stroma is likely involved in the inconspicuous early metastatic migration of CMM cells.

Long-term efficiency of mesenchymal stromal cell-mediated CD-MSC/5FC therapy in human melanoma xenograft model

“…[40][41][42] The refractoriness to the CD-MSC/5FC regimen is also likely to lie in the less efficient uptake of the toxic metabolites as a result of altered tumor-stromal interaction or resistance to apoptosis induction by ECM proteins. 43 Derived tumor cells differently interact with ECM, have altered homocellular tumor-tumor and heterocellular tumorstromal interactions, which subsequently contribute to the adhesion-mediated apoptosis resistance. [44][45][46] Shifted balance between MMPs and their inhibitors (increased expression of MMP-1, -11, -14, -16, TIMP-1 and decreased MMP-2) indicates a different matrix remodeling, 47 potentially leading to anoikis resistance in melanoma cells by mechanism similar to the one suggested by Toricelli et al 48 CD-MSC/5FC exerts potent bystander effect in the cells with functional gap junction intercellular communication.…”

Upregulation of S100P, receptor for advanced glycation end products and ezrin in malignant melanoma

“…Notably, the correlation of ezrin with S100P or RAGE was not remarkable in metastatic melanoma despite the highly coordinated overexpression of S100P and RAGE. Recent studies revealed a pivotal role of extracellular matrix and integrins in the melanoma cell invasion and metastasis . As ezrin plays an essential role in activating integrins, overexpression of ezrin may be involved, at least in part, in tumor progression of MM …”

“…Recent studies revealed a pivotal role of extracellular matrix and integrins in the melanoma cell invasion and metastasis. 32,33 As ezrin plays an essential role in activating integrins, overexpression of ezrin may be involved, at least in part, in tumor progression of MM. 34 In conclusion, our results suggested that the coordinate upregulation of S100P, RAGE and, to a less extent, ezrin may facilitate tumor progression of melanocytic tumors.…”

Streamlining Molecular Pathobiology of Malignant Melanoma

“…Currently, immunopathology helps distinguishing among a set of atypical melanocytic neoplasms, and supports attempts to precise CMM staging [4][5][6][7][8][9][10][11]. The aspect of the peritumoral stroma is moreover informative [12,13] . However, predictive markers of therapeutic response are not yet established by these methods so far.…”