Chemotherapy-induced metastasis: molecular mechanisms and clinical therapies

Abstract

Chemotherapy, the most widely accepted treatment for malignant tumors, is dependent on cell death induced by various drugs including antimetabolites, alkylating agents, mitotic spindle inhibitors, antitumor antibiotics, and hormonal anticancer drugs. In addition to causing side effects due to non-selective cytotoxicity, chemotherapeutic drugs can initiate and promote metastasis, which greatly reduces their clinical efficacy. The knowledge of how they induce metastasis is essential for developing strategies that improve the outcomes of chemotherapy. Herein, we summarize the recent findings on chemotherapy-induced metastasis and discuss the underlying mechanisms including tumor-initiating cell expansion, the epithelial-mesenchymal transition, extracellular vesicle involvement, and tumor microenvironment alterations. In addition, the use of combination treatments to overcome chemotherapy-induced metastasis is also elaborated.

Keywords: anti-cancer drugs; chemotherapy; combination therapy; metastasis.

Fig. 1. Mechanism of chemotherapy-induced metastasis.

Chemotherapy screens out cancer cells with more invasive and metastatic phenotypes, along with stem-like tumor-initiating cell (TIC) expansion, from the primary tumor. The remaining tumor cells undergo epithelial-mesenchymal transition (EMT) or elicit extracellular vesicles (EVs) to gain the ability to disseminate to distant organs. Moreover, chemotherapy-induced increased vascular permeability and vascular endothelial growth factor (VEGF) release facilitate the intravasation and dissemination of cancer cells. Additionally, chemotherapy alters the tumor microenvironment (TME) and immune composition in pro-metastatic niches or metastatic sites, including macrophage polarization and T-cell failure. Cancer-associated fibroblasts (CAFs), modulated extracellular matrix (ECM), and pro-metastatic cytokines released by tumor and stromal cells create a favorable microenvironment for tumor cells to form secondary metastatic sites.