title: Chemotherapy activates cancer-associated fibroblasts to maintain colorectal cancer-initiating cells by IL-17A.
abstract: Many solid cancers display cellular hierarchies with self-renewing, tumorigenic stemlike cells, or cancer-initiating cells (CICs) at the apex. Whereas CICs often exhibit relative resistance to conventional cancer therapies, they also receive critical maintenance cues from supportive stromal elements that also respond to cytotoxic therapies. To interrogate the interplay between chemotherapy and CICs, we investigated cellular heterogeneity in human colorectal cancers. Colorectal CICs were resistant to conventional chemotherapy in cell-autonomous assays, but CIC chemoresistance was also increased by cancer-associated fibroblasts (CAFs). Comparative analysis of matched colorectal cancer specimens from patients before and after cytotoxic treatment revealed a significant increase in CAFs. Chemotherapy-treated human CAFs promoted CIC self-renewal and in vivo tumor growth associated with increased secretion of specific cytokines and chemokines, including interleukin-17A (IL-17A). Exogenous IL-17A increased CIC self-renewal and invasion, and targeting IL-17A signaling impaired CIC growth. Notably, IL-17A was overexpressed by colorectal CAFs in response to chemotherapy with expression validated directly in patient-derived specimens without culture. These data suggest that chemotherapy induces remodeling of the tumor microenvironment to support the tumor cellular hierarchy through secreted factors. Incorporating simultaneous disruption of CIC mechanisms and interplay with the tumor microenvironment could optimize therapeutic targeting of cancer.
authors: Department of Stem Cell Biology and Regenerative Medicine, 2 Department of Cellular and Molecular Medicine, and 3 Department of Cancer Biology, Lerner Research Institute; 4 Department of Colorectal Surgery, Digestive Disease Institute; 5 Department of Anatomical Pathology, Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH 44195.
authors: Fiorenza
authors: F
authors: Lotti
authors: Awad M
authors: AM
authors: Jarrar
authors: Rish K
authors: RK
authors: Pai
authors: Masahiro
authors: M
authors: Hitomi
authors: Justin
authors: J
authors: Lathia
authors: Adam
authors: A
authors: Mace
authors: Gerald A
authors: GA
authors: Gantt
authors: Kumar
authors: K
authors: Sukhdeo
authors: Jennifer
authors: J
authors: DeVecchio
authors: Amit
authors: A
authors: Vasanji
authors: Patrick
authors: P
authors: Leahy
authors: Anita B
authors: AB
authors: Hjelmeland
authors: Matthew F
authors: MF
authors: Kalady
authors: Jeremy N
authors: JN
authors: Rich
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry*; D045744:Cell Line, Tumor; D002469:Cell Separation; D018925:Chemokines / Q000378:metabolism; D018920:Coculture Techniques; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D016207:Cytokines / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D007150:Immunohistochemistry; D020381:Interleukin-17 / Q000378:metabolism*; D051379:Mice; D009368:Neoplasm Transplantation; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D018925:Chemokines; D016207:Cytokines; D018960:Hyaluronan Receptors; D020381:Interleukin-17