Extracellular vesicle-mediated crosstalk between melanoma and the immune system: Impact on tumor progression and therapy response.

Melanoma is a very lethal tumor type that easily spreads and colonizes regional and distant tissues. Crucial phenotypic changes that favor melanoma metastasis are interposed by the tumor microenvironment (TME), representing a complex network in which malignant cells communicate not only with each other but also with stromal and immune cells. This cell-cell communication can be mediated by extracellular vesicles (EVs), which are lipid bilayer-delimited particles capable of carrying a wide variety of bioactive compounds. Both melanoma-derived or TME-derived EVs deliver important pro- and antitumor signals implicated in various stages of tumor progression, such as proliferation, metastasis, and treatment response. In this review, we highlight the recent advances in EV-mediated crosstalk between melanoma and immune cells and other important cells of the TME, and address different aspects of this bidirectional interaction as well as how this may hinder or trigger the development and progression of melanoma. We also discuss the potential of using EVs as biomarkers and therapeutic strategies for melanoma.

Pretti MAM ，Bernardes SS ，da Cruz JGV ，Boroni M ，Possik PA ... -  《-》

Extracellular Vesicles-Based Cell-Cell Communication in Melanoma: New Perspectives in Diagnostics and Therapy.

Kluszczynska K ，Czyz M 《INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES》

Reshaping the tumor microenvironment: extracellular vesicles as messengers of cancer cells.

The tumor microenvironment (TME) comprises an assortment of immune and non-immune cells. The interactions between the cancer cells and their surrounding TME are known to be a cardinal factor in all stages of cancer progression, from initiation to metastasis. Tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs) are considered two of the most abundant TME members associated with poor prognosis in various cancer types. Intercellular communication between the cancer cells and TME cells might occur via direct cell-cell contact or achieved through secreted factors such as cytokines, growth factors and extracellular vesicles (EVs). EVs are released by almost every cell type and by cancer cells in particular. EVs are loaded with unique molecular cargos that might include DNA, proteins, RNA and lipids, commonly reflecting the physiological traits of their donor cells. Once released, EVs are capable of initiating short- and long-distance communication in an autocrine, paracrine and endocrine fashion. The molecular cargos within the EVs are able to impart phenotypic changes at the receiving end thus allowing EV-releasing cancer cells to deliver messages to TME cells and tighten their grasp over the cancerous tissue. In this concise review, we aim to document the bidirectional EV-based communication between cancer cell, TAMs and CAFs, tilting the balance in favor of cancer progression and metastasis.

Bhatta B ，Cooks T 《-》

Melanoma-derived extracellular vesicles instigate proinflammatory signaling in the metastatic microenvironment.

The major cause of melanoma mortality is metastasis to distant organs, including lungs and brain. Reciprocal interactions of metastasizing tumor cells with stromal cells in secondary sites play a critical role in all stages of tumorigenesis and metastasis. Changes in the metastatic microenvironment were shown to precede clinically relevant metastases, and may occur prior to the arrival of disseminated tumor cells to the distant organ, thus creating a hospitable "premetastatic niche." Exosomes secreted by tumor cells were demonstrated to play an important role in the preparation of a hospitable metastatic niche. However, the functional role of melanoma-derived exosomes on metastatic niche formation, and the downstream pathways activated in stromal cells at the metastatic niche are largely unresolved. Here we show that extracellular vesicles (EVs) secreted by metastatic melanoma cells that spontaneously metastasize to lungs and to brain, activate proinflammatory signaling in lung fibroblasts and in astrocytes. Interestingly, unlike paracrine signaling by melanoma cells, EVs secreted by metastatic melanoma cells instigated a proinflammatory gene signature in lung fibroblasts but did not activate wound-healing functions, suggesting that tumor cell-secreted EVs activate distinct CAF characteristics and tumor-promoting functions. Moreover, melanoma-secreted EVs also activated proinflammatory signaling in astrocytes, indicating that EV-mediated reprogramming of stromal cells is a general mechanism of modulating the metastatic niche in multiple distant organs. Thus, our study demonstrates that melanoma-derived EVs reprogram tumor-promoting functions in stromal cells in a distinct manner, implicating a central role for tumor-derived EV signaling in promoting the formation of an inflammatory metastatic niche.

Gener Lahav T ，Adler O ，Zait Y ，Shani O ，Amer M ，Doron H ，Abramovitz L ，Yofe I ，Cohen N ，Erez N ... -  《-》

The Roles of Extracellular Vesicles in Malignant Melanoma.

Cheng YC ，Chang YA ，Chen YJ ，Sung HM ，Bogeski I ，Su HL ，Hsu YL ，Wang HD ... -  《Cells》