Implication of tumor microenvironment in chemoresistance: tumor-associated stromal cells protect tumor cells from cell death

Abstract

Tumor development principally occurs following the accumulation of genetic and epigenetic alterations in tumor cells. These changes pave the way for the transformation of chemosensitive cells to chemoresistant ones by influencing the uptake, metabolism, or export of drugs at the cellular level. Numerous reports have revealed the complexity of tumors and their microenvironment with tumor cells located within a heterogeneous population of stromal cells. These stromal cells (fibroblasts, endothelial or mesothelial cells, adipocytes or adipose tissue-derived stromal cells, immune cells and bone marrow-derived stem cells) could be involved in the chemoresistance that is acquired by tumor cells via several mechanisms: (i) cell-cell and cell-matrix interactions influencing the cancer cell sensitivity to apoptosis; (ii) local release of soluble factors promoting survival and tumor growth (crosstalk between stromal and tumor cells); (iii) direct cell-cell interactions with tumor cells (crosstalk or oncologic trogocytosis); (iv) generation of specific niches within the tumor microenvironment that facilitate the acquisition of drug resistance; or (v) conversion of the cancer cells to cancer-initiating cells or cancer stem cells. This review will focus on the implication of each member of the heterogeneous population of stromal cells in conferring resistance to cytotoxins and physiological mediators of cell death.

Keywords: apoptosis; cancer; chemoresistance; microenvironment.

Figure 1

Non-exhaustive interactions between cancer and its microenvironment. The recruitment of endothelial cells and pericytes by the tumor leads to the formation of new vessels and an increased supply of oxygen and nutrients. Within the tumor site, immune cells usually acquire a tumor-associated immunosuppressive phenotype, except for cytotoxic CD8⁺ lymphocytes which kill cancer cells. Pro-tumoral effects of adipocytes, carcinoma associated fibroblasts (CAFs) or mesenchymal stem cells (MSCs) include the secretion of growth factors enhancing tumor growth and the secretion of matrix metalloproteases (MMPs) which degrade the extracellular matrix and potentialize metastasis.

Figure 2

Chemoprotective effects of mesenchymal stem cells (MSCs) in ovarian cancer. In the ovarian stroma, MSCs present multiple phenotypes: they could be recruited from the bone marrow (BM-MSCs), established within the peritoneum (endogenous MSCs) or differentiated into a carcinoma-associated phenotype (CA-MSCs) via ovarian cancer cell secreted factors or molecules contained in the ascites. All these cells promote ovarian cancer cell resistance to carboplatin by several mechanisms including the secretion of unsaturated fatty acids (for endogenous MSCs activated by a carboplatin treatment) or that of factors with the exchange of MDR efflux pumps (for CA-MSCs).

Figure 3

Effects of the stromal immune cell composition on the resistance to chemotherapy. (A) The sensitivity of non-small cell lung cancer to platinum chemotherapy is determined by the balance between regulatory CD4⁺/Fox3p⁺ lymphocytes and cytotoxic CD8⁺ lymphocytes; (B) Tumor associated macrophages (TAMs) are recruited into the tumor by secretion of colony stimulating factor 1 (CSF1) from tumor cells. TAMs inhibit the survival of CD8⁺ lymphocytes and lead to a reduced sensitivity to paclitaxel. Blocking CSF1 receptor (CSF1R) by a monoclonal antibody inhibits TAMs recruitment and allows a better cytotoxic activity and chemotherapy efficiency.

Figure 3

Effects of the stromal immune cell composition on the resistance to chemotherapy. (A) The sensitivity of non-small cell lung cancer to platinum chemotherapy is determined by the balance between regulatory CD4⁺/Fox3p⁺ lymphocytes and cytotoxic CD8⁺ lymphocytes; (B) Tumor associated macrophages (TAMs) are recruited into the tumor by secretion of colony stimulating factor 1 (CSF1) from tumor cells. TAMs inhibit the survival of CD8⁺ lymphocytes and lead to a reduced sensitivity to paclitaxel. Blocking CSF1 receptor (CSF1R) by a monoclonal antibody inhibits TAMs recruitment and allows a better cytotoxic activity and chemotherapy efficiency.

Figure 4

Effects of adipocytes on cancer cell resistance to apoptosis. The secretion of interleukin-6 (IL-6) by adipocytes activates Chk1 protein in breast cancer cells, which results in an enhanced resistance to radiotherapy. Adipocyte-secreted molecules enhance breast cancer cell resistance to serum deprivation via the activation of a pro-survival program. A cell-cell contact between adipocytes and leukemia cells is responsible for the transcription of anti-apoptotic proteins (Bcl-2 and Pim-2), which enhance the resistance to chemotherapy.