Chemotherapy-Exacerbated Breast Cancer Metastasis: A Paradox Explainable by Dysregulated Adaptive-Response

Abstract

An emerging picture in cancer biology is that, paradoxically, chemotherapy can actively induce changes that favor cancer progression. These pro-cancer changes can be either inside (intrinsic) or outside (extrinsic) the cancer cells. In this review, we will discuss the extrinsic pro-cancer effect of chemotherapy; that is, the effect of chemotherapy on the non-cancer host cells to promote cancer progression. We will focus on metastasis, and will first discuss recent data from mouse models of breast cancer. Despite reducing the size of primary tumors, chemotherapy changes the tumor microenvironment, resulting in an increased escape of cancer cells into the blood stream. Furthermore, chemotherapry changes the tissue microenvironment at the distant sites, making it more hospitable to cancer cells upon their arrival. We will then discuss the idea and evidence that these devastating pro-metastatic effects of chemotherapy can be explained in the context of adaptive-response. At the end, we will discuss the potential relevance of these mouse data to human breast cancer and their implication on chemotherapy in the clinic.

Keywords: ATF3; adaptive-response network; breast cancer metastasis; cancer-host interaction; chemotherapy; immune modulation; seed and soil theory; stress response; tumor immune environment; tumor microenvironment.

Figure 1

A schematic of TMEM (tumor microenvironment metastasis). The schematic shows a TMEM composed of a macrophage and a cancer cell at peri-vascular location (first named by Robinson et al. [29]).

Figure 2

A schematic for the mechanisms by which chemotherapy elicits its pro-cancer effect via modulations of macrophages and endothelial cells. Blue text indicates the changes induced by chemotherapy; blue arrow denotes increase induced by chemotherapy; black arrow indicates promoting the events; black down arrow indicates decrease. Mϕ, macrophage; TEM, Tie2-expressing macrophage; TMEM, tumor microenvironment metastasis; EC, endothelial cells; iM, inflammatory monocyte; DCs, dendritic cells; CTC, circulating cancer cells; TIC, tumor initiation cell; TIMP, tissue inhibitor of metallopeptidase; the green and pink shades denote that the corresponding cells are altered.

Figure 3

A schematic for the “dysregulated adaptive-response hypothesis.” Briefly, dysregulation of cellular adaptive-response network plays a central role for seemingly different stressors, such as chemotherapy, tissue injuries, and tumor signals to enhance cancer progression and metastasis. The “wound healing program” denotes a generic program entailing the indicated processes (in bullet points). However, detailed molecules or genes involved may vary in different context. ECM, extracellular matrix; BM, bone marrow.