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Review
. 2017 Feb;74(4):697-713.
doi: 10.1007/s00018-016-2346-3. Epub 2016 Aug 31.

How cancer cells dictate their microenvironment: present roles of extracellular vesicles

Yutaka Naito  1 , Yusuke Yoshioka  1 , Yusuke Yamamoto  1 , Takahiro Ochiya  2
Affiliations
Review

How cancer cells dictate their microenvironment: present roles of extracellular vesicles

Yutaka Naito et al. Cell Mol Life Sci. 2017 Feb.

Abstract

Intercellular communication plays an important role in cancer initiation and progression through secretory molecules, including growth factors and cytokines. Recent advances have revealed that small membrane vesicles, termed extracellular vesicles (EVs), served as a regulatory agent in the intercellular communication of cancer. EVs enable the transfer of functional molecules, including proteins, mRNA and microRNAs (miRNAs), into recipient cells. Cancer cells utilize EVs to dictate the unique phenotype of surrounding cells, thereby promoting cancer progression. Against such "education" by cancer cells, non-tumoral cells suppress cancer initiation and progression via EVs. Therefore, researchers consider EVs to be important cues to clarify the molecular mechanisms of cancer biology. Understanding the functions of EVs in cancer progression is an important aspect of cancer biology that has not been previously elucidated. In this review, we summarize experimental data that indicate the pivotal roles of EVs in cancer progression.

Keywords: Apoptotic body; Endothelial cells; Epithelial cells; Exosome; Fibroblasts; Immune cells; Mesenchymal stem cells; Microvesicle.

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Figures

Fig. 1
Fig. 1
Cancer cell-derived EVs modify the characters of cancer surrounding microenvironment. Several kinds of cell types, such as cancer cells, fibroblasts, immune cells, endothelial cells, epithelial cells, and mesenchymal stem cells, comprise unique microenvironment for cancer progression. Cancer cells utilize EVs to modify surrounding cells within tumor microenvironment. Cancer-derived EVs have multiple functions that depend on component molecules of EVs. To induce cancer-associated fibroblast (CaF)-like phenotypes in cancer surrounding fibroblasts and mesenchymal stem cells, cancer cells secrete EVs and transfer growth factors and microRNAs (miRNAs), including transforming growth factor-beta (TGF-β) and miR-155, respectively. To escape from immune surveillance, cancer cells transfer several types of immunoregulatory molecules into immune cells. However, these cancer-derived EVs also stimulate cancer immunity to kill tumor cells because tumor antigens were packaged in EVs and stimulated cancer immunity. Cancer-derived EVs also contain angiogenic proteins and miRNAs that promote migration and proangiogenic activity of endothelial cells. In addition, miR-105 and miR-181c in EVs are capable of rupturing the vascular system to increase the permeability that supports cancer metastasis. Cancer-derived EVs confer malignant phenotypes in other cancer cells and epithelial cells by transferring oncogenic proteins and miRNAs, such as EGFRvIII, miR-200, and tissue transglutaminase (tTG). Taken together, cancer cells “dictate” the characters of their surrounding stromal cells and create a convenient microenvironment to support cancer progression via EVs
Fig. 2
Fig. 2
The functional role of non-tumoral cell-derived EVs in cancer initiation and progression. Non-tumoral cells utilize EVs to affect cancer initiation and progression. Cancer-associated fibroblasts secrete EVs and affect invasion, proliferation, chemoresistance, and metabolic properties of cancer cells by transferring CD81, miR-21, miR-409, and metabolites. Macrophage-derived EVs contain miR-223, which stimulates the invasive activity of cancer cells. Monocytes transfer miR-155 to neuroblastoma via EVs and induce chemoresistance in neuroblastoma. “Non-educated” mesenchymal stem cells (MSCs) by cancer cells secrete EVs containing miR-16 to suppress tumor growth and angiogenesis. However, interestingly, “educated” MSCs by cancer cells enable to secrete EVs that contain tumor promotive proteins such as plakoglobin and CCL2. MSC-derived EVs also transfer miR-23b, which induce dormant state of cancer cells to survive in a quiescent state while waiting for the appropriate environmental conditions to begin proliferation again. Non-aberrant epithelial cells secreted EVs to transfer miR-143 into cancer cells and suppress tumor growth
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