CSE1L, a Novel Microvesicle Membrane Protein, Mediates Ras-Triggered Microvesicle Generation and Metastasis of Tumor Cells

Abstract

Tumor-derived microvesicles are rich in metastasis-related proteases and play a role in the interactions between tumor cells and tumor microenvironment in tumor metastasis. Because shed microvesicles may remain in the extracellular environment around tumor cells, the microvesicle membrane protein may be the potential target for cancer therapy. Here we report that chromosome segregation 1-like (CSE1L) protein is a microvesicle membrane protein and is a potential target for cancer therapy. v-H-Ras expression induced extracellular signal-regulated kinase (ERK)-dependent CSE1L phosphorylation and microvesicle biogenesis in various cancer cells. CSE1L overexpression also triggered microvesicle generation, and CSE1L knockdown diminished v-H-Ras-induced microvesicle generation, matrix metalloproteinase (MMP)-2 and MMP-9 secretion and metastasis of B16F10 melanoma cells. CSE1L was preferentially accumulated in microvesicles and was located in the microvesicle membrane. Furthermore, anti-CSE1L antibody-conjugated quantum dots could target tumors in animal models. Our findings highlight a novel role of Ras-ERK signaling in tumor progression and suggest that CSE1L may be involved in the "early" and "late" metastasis of tumor cells in tumorigenesis. Furthermore, the novel microvesicle membrane protein, CSE1L, may have clinical utility in cancer diagnosis and targeted cancer therapy.

Correlations between cytoplasmic CSE1L in neoplastic colorectal glands and depth of tumor penetration and cancer stage

“…A recent report on B16F10 melanoma cells showed that CSE1L overexpression triggered microvesicle generation, whereas CSE1L knockdown diminished Ras-induced microvesicle generation, MMP-2/MMP-9 secretion, and metastasis [33]. Recent studies have proposed that secretory CSE1L might be a potential prognostic marker of cancer [33,40,41,43]. This study further showed that cytoplasmic CSE1L was involved in the invasiveness of CRC cells.…”

“…The results indicate that CSE1L plays a role in regulating the metastasis of colorectal cancer cells. Moreover, CSE1L is known to stimulate the extension of invadopodia and the secretion of matrix metalloproteinases of several cancer cell lines [15,33]. Thus, stimulation of tumor invasion and metastasis should be the correct role of CSE1L in tumor development.…”

“…Microvesicles are rich in metastasis-related proteases and play a role in the interaction between tumor cells and the tumor microenvironment during metastasis [42]. A recent report on B16F10 melanoma cells showed that CSE1L overexpression triggered microvesicle generation, whereas CSE1L knockdown diminished Ras-induced microvesicle generation, MMP-2/MMP-9 secretion, and metastasis [33]. Recent studies have proposed that secretory CSE1L might be a potential prognostic marker of cancer [33,40,41,43].…”

Does CSE1L Overexpression Affect Distant Metastasis Development in Breast Cancer?

“…It was shown that CSE1L is related to microvesicle biogenesis and causes temporary extension of the plasma membrane which contributes to cancer cell migration and invasion [20]. Moreover, increased CSE1L expression enhances the secretion of matrix metalloproteinase-2 and the invasiveness of cancer cells [20].…”

“…Moreover, increased CSE1L expression enhances the secretion of matrix metalloproteinase-2 and the invasiveness of cancer cells [20]. Furthermore, reduction in CSE1L expression resulted in metastasis inhibition in B16 and F10 melanoma cells in mice [21], and overexpression of CSE1L in MCF-7 breast cancer cells increased the migration and invasiveness of cancer cells [20]. CSE1L is mapped on chromosome 20q13 which is known to harbor amplifications that correlate with aggressive breast cancer [22].…”