Abstract
BackgroundIntegrins, cell-surface receptors that mediate adhesive interactions between cells and the extracellular matrix (ECM), play an important role in cancer progression. Expression of the vitronectin receptor αvβ3 integrin correlates with increased invasive and metastatic capacity of malignant melanomas, yet it remains unclear how expression of this integrin triggers melanoma invasion and metastasis.ResultsTwo melanoma cell lines C8161.9 and M14 both express high levels of αvβ3 integrin and adhere to vitronectin. However, only the highly metastatic C8161.9 cells are capable of invading vitronectin-enriched Matrigel in an αvβ3-depenent manner. Elevated levels of PKCα and PKCδ, and activated Src were detected specifically in the highly metastatic melanoma cells, but not in the low metastatic M14 cells. Inhibition of Src or PKC activity suppressed αvβ3-dependent invasion. Furthermore, over expression of Src or PKCα and PKCδ was sufficient to confer αvβ3-dependent invasiveness to M14 cells. Stress fiber formation and focal adhesion formation were almost completely absent in C8161.9 cells compared to M14 cells. Inhibition of Src signaling was sufficient to restore normal actin architecture, and resulted in decreased p190RhoGAP phosphorylation and enhanced RhoA activity. Src had no effect on Rac activity. Loss of PKCα expression, but not PKCδ, by siRNA inhibited Rac and PAK activity as well as invasiveness. Loss of PKCα restored focal adhesion formation and partially restored stress fiber formation, while loss of PKCδ primarily restored stress fibers.ConclusionThe misregulated expression of PKCα and PKCδ and elevated Src activity in metastatic melanoma cells is required for efficient αvβ3-mediated invasion. PKCα and Src enhance αvβ3-mediated invasion in part by increasing the GTPase activity of Rac relative to RhoA. PKCα influences focal adhesion formation, while PKCδ controls stress fibers.
Highlights
Integrins, cell-surface receptors that mediate adhesive interactions between cells and the extracellular matrix (ECM), play an important role in cancer progression
To determine which integrin is responsible for the biological effects mediated by adhesion to VN, αvβ3 and αvβ5 integrin expression was measured in the melanoma cells
M14 and normal melanocytes both failed to invade through VN/Matrigel, while invasion of the highly metastatic C8161.9 cells was dramatically diminished in the presence of αvβ3, but not αvβ5 blocking antibodies (Figure 1B)
Summary
Cell-surface receptors that mediate adhesive interactions between cells and the extracellular matrix (ECM), play an important role in cancer progression. Αvβ is not expressed on melanocytes, nevi, or radial growth primary melanomas in vivo. Induced expression of αvβ integrin is coincident with and present only on vertical growth phase melanomas [2,3]. It is present in melanocyte precursors, i.e. neural crest cells, as they migrate and populate the skin during early development. The M21-L human melanoma cell line, lacking αvβ integrin expression, was shown to have a dramatically reduced ability to induce tumors and metastases in nude mice. Ectopic expression of αvβ in radial growth melanomas isolated from patients is sufficient to confer enhanced growth and invasive properties to those tumor cells [5]. The precise mechanisms by which αvβ integrin expression promotes melanoma growth and metastasis remain poorly understood
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