The Multiple Roles of Exosomes in Metastasis

Abstract

Abstract. Exosomes are important contributors to cellMetastases are responsible for the death of a large majority of cancer patients despite considerable progress in surgical techniques, radiotherapy, chemotherapy and targeted therapies including immuno-therapy (1). A dramatic reduction of metastatic burden has been observed, however, tumor elimination is almost always incomplete. This phenomenon is based on drug resistance, which is due to adaptation of intracellular pathways or on activation of survival-supporting autocrine and paracrine pathways and several secreted factors expressed by drug-sensitive tumor cells after therapy (2). Metastasis can occur through release of cancer cells from the primary tumor into body cavities that holds true for ovarian and CNS tumors, or via hematogeneous and lymphatic vessels of the circulatory system (3). Metastases of some tumors are directed besides to lymph nodes to mainly one type of organ only, such as prostate cancer to the bones, pancreatic cancer and uveal melanoma to the liver, whereas tumors such as melanoma, breast-and lung cancer can colonize several types of organs (3). Tumor cells have been found in the blood of patients with early-stage cancer and in some cases even before the primary tumor has been diagnosed (4, 5). Recently, making use of single-cell expression profiling, it has been shown that early metastatic cells possess a stem-like gene signature and give rise to heterogeneous metastases (6). The metastatic process is characterized by a defined sequence of events (7,8). Initial steps are detachment from the extracellular matrix (ECM), invasion into the surrounding tissue and proteolysis of the basement membrane. After intravasation, survival of circulating tumor cells (CTCs) is achieved by forming clusters, binding to platelets and immune evasion. Subsequently, they arrest in distal microvascular beds and extravasation can be achieved either by migration through intercellular junctions of endothelial cells (EC) or penetration of a single EC (9). CTCs can also colonize their tumors of origin, a process referred to as "tumor self-seeding", selecting for cancer cell populations more aggressive than those present in the primary tumor (10). After extravasation, colonization and outgrowth in the parenchyma of distant organs are the following steps. A common theme of the metastatic process is settlement of disseminated tumor cells (DTCs) into latency (dormancy), which can last from several months to decades (11). It has been observed that DTCs are recruited into pre-metastatic niches that support their survival by interactions with endothelial, myeloid cells, fibroblasts and other types of cells. After adaptation to the host microenvironment and suppression of an anti-tumoral immune response, DTCs are activated by not yet completely resolved mechanisms. Finally their outgrowth is based on an angiogenic switch mediated by pro-angiogenic factors and establishment of a vascular network to support the metabolic demands of colonizing tumor cells (12). In the follo...

Macrophage-Dependent Cytoplasmic Transfer during Melanoma Invasion In Vivo

“…We next asked how macrophage cytoplasm is delivered to tumor cells. There are at least two mechanisms of cytoplasmic transfer – transfer of molecules extracellularly via secretion of extracellular vesicles (EVs), and transfer of molecules through cell-to-cell contact (Lou et al, 2017; McCoy-Simandle et al, 2016; Weidle et al, 2017)). The migration-promoting cytoplasmic transfer between tumor cells described by Zomer et al was via systemic transfer of EVs, however given the close and sustained physical interactions between macrophages and tumor cells observed in our zebrafish studies, we hypothesized that the cytoplasmic transfer from macrophages to tumor cells is cell-contact mediated.…”

Ceramide and Exosomes: A Novel Target in Cancer Biology and Therapy

“…Li, Zhang, Zheng, Liu, & Chen, 2017; Pietrowska et al, 2017; Pocsfalvi et al, 2016; Sandfeld-Paulsen, Aggerholm-Pedersen, et al, 2016; Sandfeld-Paulsen, Jakobsen, et al, 2016; Sinha et al, 2018; Tanase et al, 2017; Taylor, Zacharias, & Gercel-Taylor, 2011; van Niel et al, 2018; Weidle et al, 2017)) (Fig. 1).…”

“…In cancer, exosomes reprogram tissue to allow growth of metastases, act as decoys to escape the immune system, or spread factors conferring resistance to drugs used in chemotherapy (Chiarugi & Cirri, 2016; Desrochers et al, 2016; Dorsam, Reiners, & von Strandmann, 2018; Dreyer & Baur, 2016; Kahlert & Kalluri, 2013; Kalluri, 2016; Ruivo, Adem, Silva, & Melo, 2017; S, Mager, Breakefield, & Wood, 2013; M. Silva & Melo, 2015; Steinbichler, Dudas, Riechelmann, & Skvortsova, 2017; Weidle, Birzele, Kollmorgen, & Ruger, 2017; H. G. Zhang & Grizzle, 2014; Zhao et al, 2017).…”

Further the liquid biopsy: Gathering pieces of the puzzle of genometastasis theory

“…What is more, these vesicles can travel to distant sites of the organism and release the packed biomolecules into local and remote cells. Exosomes can bear different proteins including transmembrane proteins, such as major histocompatibility complex (MHC), and other intraluminal proteins and oncoproteins such as mutant KRAS[47]. Proteins delivered by exosomes can activate or inhibit different signalling pathways, altering cell function.…”

“…As an example, it was demonstrated that exosomes increased cellular proliferation in gastric cancer cell lines by activating Akt phosphorylation[48]. Moreover, it has been described that TD exosomes can also facilitate cancer invasion and metastasis by regulating stromal cells, remodelling the extracellular matrix and stimulating angiogenesis[47,49]. …”