Abstract
Melanomas are highly lethal skin tumours that are frequently treated by surgical resection. However, the efficacy of such procedures is often limited by tumour recurrence and metastasis. Caveolin-1 (CAV1) has been attributed roles as a tumour suppressor, although in late-stage tumours, its presence is associated with enhanced metastasis. The expression of this protein in human melanoma development and particularly how the presence of CAV1 affects metastasis after surgery has not been defined. CAV1 expression in human melanocytes and melanomas increases with disease progression and is highest in metastatic melanomas. The effect of increased CAV1 expression can then be evaluated using B16F10 murine melanoma cells injected into syngenic immunocompetent C57BL/6 mice or human A375 melanoma cells injected into immunodeficient B6Rag1−/− mice. Augmented CAV1 expression suppresses tumour formation upon a subcutaneous injection, but enhances lung metastasis of cells injected into the tail vein in both models. A procedure was initially developed using B16F10 melanoma cells in C57BL/6 mice to mimic better the situation in patients undergoing surgery. Subcutaneous tumours of a defined size were removed surgically and local tumour recurrence and lung metastasis were evaluated after another 14 days. In this postsurgery setting, CAV1 presence in B16F10 melanomas favoured metastasis to the lung, although tumour suppression at the initial site was still evident. Similar results were obtained when evaluating A375 cells in B6Rag1−/− mice. These results implicate CAV1 expression in melanomas as a marker of poor prognosis for patients undergoing surgery as CAV1 expression promotes experimental lung metastasis in two different preclinical models.
Highlights
Cancer is a leading cause of death worldwide, whereby the large majority of patients succumb as a consequence of metastasis to secondary sites rather than tumour growth at the initial site
Human fibroblasts were included as a positive control for CAV1 expression. (c) Relative CAV1 expression levels are graphed for the different human melanoma preparations
We compared by western blot analysis CAV1 levels in human melanocytes with those of primary malignant radial growth phase (RGP), vertical growth phase (VGP) and metastatic cells (Mts) cells and detected a highly significant increase in CAV1 expression with increasing progression of disease (Fig. 1a)
Summary
Cancer is a leading cause of death worldwide, whereby the large majority of patients succumb as a consequence of metastasis to secondary sites rather than tumour growth at the initial site. Skin cancer is currently considered the third most common human malignancy and its incidence is increasing worldwide at an alarming rate because of environmental and behavioural changes. Within this group of cancers, melanomas are the most dangerous form and account for the majority of skin cancer-related deaths. As for other cancers, metastasis is considered the major threat to patient survival. Identification of relevant prognostic molecular markers in this context is of great interest. Caveolins are a family of proteins that are generally implicated in the formation of plasma membrane-associated
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