Chemotherapy-induced metastasis: mechanisms and translational opportunities

Abstract

Tumors often overcome the cytotoxic effects of chemotherapy through either acquired or environment-mediated drug resistance. In addition, signals from the microenvironment obfuscate the beneficial effects of chemotherapy and may facilitate progression and metastatic dissemination. Seminal mediators in chemotherapy-induced metastasis appear to be a wide range of hematopoietic, mesenchymal and immune progenitor cells, originating from the bone marrow. The actual purpose of these cells is to orchestrate the repair response to the cytotoxic damage of chemotherapy. However, these repair responses are exploited by tumor cells at every step of the metastatic cascade, ranging from tumor cell invasion, intravasation and hematogenous dissemination to extravasation and effective colonization at the metastatic site. A better understanding of the mechanistic underpinnings of chemotherapy-induced metastasis will allow us to better predict which patients are more likely to exhibit pro-metastatic responses to chemotherapy and will help develop new therapeutic strategies to neutralize chemotherapy-driven prometastatic changes.

Keywords: Bone marrow-derived cells; Cancer cell dissemination; Macrophages; MenaCalc; Mesenchymal stem cells; TMEM.

Figure 1

Chemotherapy-induced metastasis. A working model depicting critical molecular and cellular events of the metastatic cascade, including those in (1) primary tumor site (yellow box), (2) blood circulation (red box), and (3) secondary tumor site (green box). Illustrations of chemotherapy-induced cellular and molecular events that facilitate the metastatic cascade are shown for each compartment individually. Chemotherapy treatment induces the infiltration of a wide variety of bone marrow-derived cells (BMDCs) and mesenchymal stem cells (MSCs), mostly including proangiogenic and intratumoral macrophages, by altering the tumor chemokine network (including CXCR4/CCR2/CSF1R), thus amplifying all prometastatic pathways which involve the TMEM dissemination machinery (primary and secondary tumor sites) and the premetastatic niche formation (secondary tumor site). In addition, chemotherapy treatment may induce a platelet-mediated prometastatic response in blood circulation, as evidenced by the aggregation of platelets and platelet-derived macrovesicles around circulating tumor cells (CTCs). Cartoon abbreviations: EC, endothelial cell; M, macrophage; TC, tumor cell; TMEM, tumor microenvironment of metastasis.

Figure 2

TMEM in primary and secondary tumor sites. Tissue images from primary mammary tumor (A), and lung metastatic tumor (B), showing TMEM sites as visualized by triple-stain immunohistochemistry. The black boxes represent magnified inserts of the black squared areas to display TMEM structures in higher detail. EC, blue, endothelial cell; M, brown, macrophage; TC, red, MENA-expressing tumor cell. Figure from Entenberg et al. (2017) (161).