Microvesicles Released from Human Renal Cancer Stem Cells Stimulate Angiogenesis and Formation of Lung Premetastatic Niche

Abstract

Recent studies suggest that tumor-derived microvesicles (MV) act as a vehicle for exchange of genetic information between tumor and stromal cells, engendering a favorable microenvironment for cancer development. Within the tumor mass, all cell types may contribute to MV shedding, but specific contributions to tumor progression have yet to be established. Here we report that a subset of tumor-initiating cells expressing the mesenchymal stem cell marker CD105 in human renal cell carcinoma releases MVs that trigger angiogenesis and promote the formation of a premetastatic niche. MVs derived only from CD105-positive cancer stem cells conferred an activated angiogenic phenotype to normal human endothelial cells, stimulating their growth and vessel formation after in vivo implantation in immunocompromised severe combined immunodeficient (SCID) mice. Furthermore, treating SCID mice with MVs shed from CD105-positive cells greatly enhanced lung metastases induced by i.v. injection of renal carcinoma cells. Molecular characterization of CD105-positive MVs defines a set of proangiogenic mRNAs and microRNAs implicated in tumor progression and metastases. Our results define a specific source of cancer stem cell-derived MVs that contribute to triggering the angiogenic switch and coordinating metastatic diffusion during tumor progression. Cancer Res; 71(15); 5346-56. Ó2011 AACR.

The 786-0 renal cancer cell-derived exosomes promote angiogenesis by downregulating the expression of hepatocyte cell adhesion molecule

“…Consistent with a number of previous studies (10,(25)(26)(27), 786-0 cell-derived exosomes were observed to increase the formation of tubular stuctures in HUVECs compared with the control group. However, the underlying molecular mechanism of this effect remains unclear.…”

Exosomes as secondary inductive signals involved in kidney organogenesis

“…It is known that proteins found in human urinary exosomes are specific to or enriched in given regions of the kidney [7]. Currently available data indicate that EVs may be involved in organogenesis and that kidney-derived vesicles may also impact cells of certain other organs [8]. Very recently, the involvement of exosomes secreted by the epithelium and mesenchyme of a developing tooth were shown to diffuse through the basement membrane and regulate cell differentiation and matrix synthesis.…”

Oncogenic ras-driven cancer cell vesiculation leads to emission of double-stranded DNA capable of interacting with target cells

“…Similarly, oncogenic transcripts and non-coding RNA are found in the cargo of EVs released by different cancer cells [6][7][8]. Notably, horizontal transfer of oncogenecontaining EVs evokes cellular responses reminiscent of malignant transformation and impacts growth, inflammation and angiogenesis [2][3][4]9,10].…”