Bête Noire of Chemotherapy and Targeted Therapy: CAF-Mediated Resistance

Abstract

In tumor cells' struggle for survival following therapy, they resist treatment. Resistance to therapy is the outcome of well-planned, highly efficient adaptive strategies initiated and utilized by these transformed tumor cells. Cancer cells undergo several reprogramming events towards adapting this opportunistic behavior, leading them to gain specific survival advantages. The strategy involves changes within the transformed tumors cells as well as in their neighboring non-transformed extra-tumoral support system, the tumor microenvironment (TME). Cancer-Associated Fibroblasts (CAFs) are one of the components of the TME that is used by tumor cells to achieve resistance to therapy. CAFs are diverse in origin and are the most abundant non-transformed element of the microenvironment in solid tumors. Cells of an established tumor initially play a direct role in the establishment of the CAF population for its own microenvironment. Like their origin, CAFs are also diverse in their functions in catering to the pro-tumor microenvironment. Once instituted, CAFs interact in unison with both tumor cells and all other components of the TME towards the progression of the disease and the worst outcome. One of the many functions of CAFs in influencing the outcome of the disease is their participation in the development of resistance to treatment. CAFs resist therapy in solid tumors. A tumor-CAF relationship is initiated by tumor cells to exploit host stroma in favor of tumor progression. CAFs in concert with tumor cells and other components of the TME are abettors of resistance to treatment. Thus, this liaison between CAFs and tumor cells is a bête noire of therapy. Here, we portray a comprehensive picture of the modes and functions of CAFs in conjunction with their role in orchestrating the development of resistance to different chemotherapies and targeted therapies in solid tumors. We investigate the various functions of CAFs in various solid tumors in light of their dialogue with tumor cells and the two components of the TME, the immune component, and the vascular component. Acknowledgment of the irrefutable role of CAFs in the development of treatment resistance will impact our future strategies and ability to design improved therapies inclusive of CAFs. Finally, we discuss the future implications of this understanding from a therapeutic standpoint and in light of currently ongoing and completed CAF-based NIH clinical trials.

Keywords: cancer-associated fibroblasts; chemotherapy; resistance; targeted therapy.

Figure 1

Distribution pattern of types of resistance to chemotherapy based on specific mediators of CAF functions in solid tumors: The four mediators employed by CAFs to orchestrate the development of resistance to chemotherapy are presented in the cartoon. The most common mode of interaction is paracrine, wherein CAFs signal to either tumor cells or other components of the TME via characteristic secretome. In addition to the involvement of the characteristic secretome, exosomal cargos delivering different miRNAs that target various cell signaling proteins are common mediators of CAF actions. Among different organ cancers, gastric cancers have been reported to be the most common tumors in which CAFs are involved in the development of resistance to chemotherapy. The sizes of the boxes indicate the number of studies in each box. The shapes indicate the types of resistance in different tumors (inset). L-OHP is a new derivative of oxaliplatin; 5-FU is fluorouracil. Organ tumors are indicated by their respective ribbon colors. Head and neck cancer: white and burgundy; stomach cancer: periwinkle blue; colon cancer: dark blue; ovarian cancer: teal; lung cancer: white or pearl; breast cancer: pink; pancreatic cancer: purple; bladder cancer: blue, yellow, and purple.

Figure 2

Distribution pattern of types of resistance to targeted therapy based on specific mediators of CAF functions in solid tumors: The four types of mediators of action employed by CAFs to orchestrate the development of resistance to targeted therapy are presented in the cartoon. The most common mode of interaction is paracrine, wherein CAFs signal to either tumor cells or other components of the TME via characteristic secretome. In addition to the involvement of characteristic secretome, exosomal cargos delivering different miRNAs that target various cell signaling proteins are common mediators of CAF action. The sizes of the boxes indicate the number of studies in each box. The shapes indicate the types of resistance in different tumors (inset). Organ tumors are indicated by their respective ribbon colors. Lung cancer: white or pearl; skin cancer: black. liver cancer: emerald green; breast cancer: pink; prostate cancer: light blue.

Figure 3

Strategic opportunities to regulate CAF functions in an established or progressing solid tumor. The strategic points to control the function of CAFs are (1) prevention of activation of CAFs by targeting or counteracting signals from tumor cells, (2) regulating the activation of CAFs by targeting the CAF population directly, (3) regulating the pro-tumorigenic signals from CAFs, (4) regulating the pro-angiogenic signals from CAFs, and (5) regulating the pro-immune evasion and anti-immune surveillance signals from CAFs. These strategic points represent ‘action items’ to ‘switch off’ the pro-resistance CAFs within the tumor stroma.