Chemotherapy-Induced Metastasis: Molecular Mechanisms, Clinical Manifestations, Therapeutic Interventions

Abstract

Chemotherapy offers long-term clinical benefits to many patients with advanced cancer. However, recent evidence has linked the cytotoxic effects of chemotherapy with the de novo elicitation of a prometastatic tumor microenvironment. This "modified" tumor microenvironment is triggered by a chemotherapy-driven cytokine storm or through direct effects of certain chemotherapeutics on stromal and/or immune cells, the most critical being tumor-associated macrophages. These chemotherapy-educated cells act as facilitators in tumor-host cell interactions promoting the establishment of distant metastasis. Certain clinical studies now offer substantial evidence that prometastatic changes are indeed identified in the tumor microenvironment of certain patient subpopulations, especially those that do not present with any pathologic response after neoadjuvant chemotherapy. Deciphering the exact contextual prerequisites for chemotherapy-driven metastasis will be paramount for designing novel mechanism-based treatments for circumventing chemotherapy-induced metastasis.

Figure 1.. Hallmarks of Chemotherapy-Induced Metastasis

(A) An illustrative model of chemotherapy-“naïve” (upper panel) and -treated (lower panel) tumor microenvironments, associated with the process of metastasis. Chemotherapy acts as a “cell stressor” that inflicts cytotoxic tissue damage and severe cancer cell apoptosis and hypoxia, resulting in the extensive release of pro-inflammatory cytokines and chemokines, collectively known as the “cytokine storm”. The cytokine storm promotes metastasis through distinct mechanisms, including, but not limited to: (i) immunosuppression and T cell exhaustion, (ii) macrophage repolarization, (iii) tumor cell education into releasing prometastatic factors (exosomes and extracellular vesicles), (iv) mobilization of endothelial progenitors, contributing to tumor angiogenesis, and (v) recruitment of bone marrow-derived myeloid cells, including perivascular Tie2^High macrophages assembling TMEM doorways (triad cells shown in black triangles), and Vegfr3^High macrophages supporting tumor lymphangiogenesis. At the bottom, there is a legend showing all the different types of cells involved in chemotherapy-induced metastasis, as explained in the figure and the manuscript text. Illustration created by BioRender.com. (B) Detailed illustration of TMEM doorway assembly and function in both chemotherapy-“naïve” and chemotherapy-treated primary tumors. TMEM doorway function is a two-step process: First, the TMEM tumor cell inserts a stable invadopodium between endothelial cells to define the site of vascular weakness and intravasation. Second, the TIE2 receptor on the TMEM macrophage has multiple stimulatory inputs, including Ang2 and integrin ligands, and controls VEGF production by the TMEM macrophage resulting in VEGF-induced vascular permeability at the site of vascular weakness and intravasation defined by the TMEM tumor cell. (C) High resolution 3D reconstruction of a TMEM doorway, prepared from intravital imaging of a mammary tumor in vivo, showing the three cell types stably bound together, located as points of a black triangle. The TMEM tumor cell invadopodium is inserted between two endothelial cells of the blood vessel to define the site of vascular weakness and intravasation.