Tumor cell vascular mimicry: Novel targeting opportunity in melanoma

Abstract

In 1999, the American Journal of Pathology published an article, entitled “Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry” by Maniotis and colleagues, which ignited a spirited debate for several years and earned the journal's distinction of a “citation classic” (Maniotis et al., 1999). Tumor cell vasculogenic mimicry (VM), also known as vascular mimicry, describes the plasticity of aggressive cancer cells forming de novo vascular networks and is associated with the malignant phenotype and poor clinical outcome. The tumor cells capable of VM share the commonality of a stem cell-like, transendothelial phenotype, which may be induced by hypoxia. Since its introduction as a novel paradigm for melanoma tumor perfusion, many studies have contributed new findings illuminating the underlying molecular pathways supporting VM in a variety of tumors, including carcinomas, sarcomas, glioblastomas, astrocytomas, and melanomas. Of special significance is the lack of effectiveness of angiogenesis inhibitors on tumor cell VM, suggesting a selective resistance by this phenotype to conventional therapy. Facilitating the functional plasticity of tumor cell VM are key proteins associated with vascular, stem cell, extracellular matrix, and hypoxia-related signaling pathways -- each deserving serious consideration as potential therapeutic targets and diagnostic indicators of the aggressive, metastatic phenotype. This review highlights seminal findings pertinent to VM, including the effects of a novel, small molecular compound, CVM-1118, currently under clinical development to target VM, and illuminates important molecular pathways involved in the suppression of this plastic, aggressive phenotype, using melanoma as a model.

Undifferentiated sinonasal malignant melanoma: A case report

“…Cancer stem cells may contribute to the formation of VM (26). VM was originally identified in malignant melanoma, and was subsequently demonstrated to be an important morphological feature of MM (27). In the present study, VM is detectable in undifferentiated MM due to stemness, which may be a useful tool for MM diagnosis.…”

Targeting angiogenesis in small cell lung cancer

“…This interplay between angiogenesis and tumor initiating cells offers the rationale for combining anti-angiogenetic agents with drugs that target CSCs (80). Novel compounds, such as CVM-1118, targeting VM and the associated stem cell and drug resistance phenotypes are under development (81).…”

Challenges and unanswered questions for the next decade of circulating tumour cell research in lung cancer

“…The term VM was first coined by Mary Hendrix and described the formation of tumour-derived blood vessels and it was hypothesised that this may provide an easy access for tumour cells to the bloodstream (125). VM was first described in human melanoma where it was shown that tumour cells shown to co-express endothelial and tumour markers and formed blood vessels (125) and further studies have given insights in VM induction across a variety of cancer types including breast, ovary, lung, prostate, bladder cancer (126). VM has been associated with tumour dissemination and metastasis (127) and in SCLC it has been shown that a subpopulation of CTCs co-express VE-cadherin (a VM marker) as well as epithelial cytokeratins indicating VM is involved in CTCs dissemination (124).…”