**5.2 Why are EVs so important in establishing the tumor microenvironment? Can the microenvironment become a target for new treatments?**

In developing new therapeutic targets, one key area of focus is the immediate, small-scale environment surrounding cancer cells known as the microenvironment. The tumor microenvironment includes the extracellular matrix, neighboring blood

#### **Figure 1.**

*The interaction between EOC cells and their microenvironment. Cancer cells release EVs that instruct normal cells to produce EVs that support cancer growth and invasion while also facilitating the development of chemoresistance and protection from the immune system [1, 2].*

vessels, stromal cells such as macrophages and fibroblasts, stem cells, signaling molecules, and immune cells [22]. For EOC the microenvironment becomes an integral component for drug targeting because of the role that it plays in protecting the tumor from chemotherapy and the immune system as well as in promoting proliferation, invasion, and metastasis. By targeting EOC EVs that transform healthy tissue into this tumorigenic niche, researchers will enhance the effectiveness of current treatments by reversing chemoresistance as well as limit the deadly growth and spread of this disease (**Figure 1**).

EVs derived from EOC cells promote the transformation from a normal microenvironment into a tumorigenic one through intercellular communication that stimulates angiogenesis, immune suppression, and stromal invasion [27]. Specifically, altered expression of miRNA such as miR-214, miR-31, and miR-155 has been linked to the conversion of fibroblasts, a support cell within the connective tissue, into cancer-associated fibroblasts (CAFs)— cells that participate in cancer propagation, support of the tumorigenic microenvironment, alteration of the extracellular matrix, and metastasis [1]. The CAFs then produce EVs enriched with TGFβ1 that then trigger the invasive properties of the tumor. With almost deliberate malintent, the cancer cells drive their own invasive potential by directing the formation of CAFs that provide the necessary growth factors that allow the malignancy to spread. Following treatment with cisplatin, a frontline chemotherapy agent, EOC cells release EVs that promote tumorigenic activity of mesenchymal stem cells that eventually stimulate cancer progression [28]. By developing therapies targeted at these factors that transform the healthy tissue surrounding cancer into the tumorigenic microenvironment, scientists can inhibit the cancer's ability create its own protective environment that fuels its ability to grow and invade.
