Chemotherapy activates cancer-associated fibroblasts to maintain colorectal cancer-initiating cells by IL-17A

Lotti, Fiorenza; Jarrar, Awad; Pai, Rish K.; Hitomi, Masahiro; Lathia, Justin D.; Mace, Adam G.; Gantt, Gerald; Sukhdeo, Kumar; DeVecchio, Jennifer; Vasanji, Amit; Leahy, Patrick; Hjelmeland, Anita B.; Kalady, Matthew F.; Rich, Jeremy

doi:10.1084/jem.20131195

Cited by 310 publications

(275 citation statements)

References 98 publications

(155 reference statements)

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“…Previous studies have demonstrated that stromal compartments are changed by cytotoxic therapies (14,15), indicating microenvironment-associated drug resistance. Therefore, the stromal response in the MTD and LDM groups treated with 5-Fu or capecitabine was examined.…”

Section: Resultsmentioning

confidence: 99%

“…The significant increase in the amount of CAFs following chemotherapy indicated that chemotherapy may induce the remodeling of the tumor microenvironment as well, and CAFs may offer microenvironmental cues instructing tumor drug resistance (14,21). In vitro assays have also demonstrated that CAFs induce resistance to chemotherapy via secreting cytokines (16,22,23).…”

Section: Discussionmentioning

confidence: 99%

“…In recent years, studies on chemotherapy resistance have focused on the tumor microenvironment. Cancer-associated fibroblasts (CAFs), the dominant component of the tumor microenvironment, have been confirmed to modulate chemoresistance by secreting cytokines, including stromal cell-derived factor-1α, interleukin (IL)-6 and IL-17A (12)(13)(14). The present study aimed to evaluate whether capecitabine or 5-Fu chemotherapy with the metronomic pattern may cause significant chemoresistance compared with the traditional pattern, and whether CAFs are involved in the drug resistance.…”

Section: Introductionmentioning

confidence: 99%

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Metronomic chemotherapy remodel cancer‑associated fibroblasts to decrease chemoresistance of gastric cancer in nude mice

Wang

Jiang

et al. 2017

Oncol Lett

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Abstract. The present study aimed to evaluate whether capecitabine or 5-fluorouracil (5-Fu) chemotherapy with the metronomic pattern may cause significant chemoresistance compared with the traditional pattern, and whether CAFs are involved in drug resistance. SGC-7901 cells were subcutaneously injected into the nude mice, and the mice were divided into five groups: The control group, intraperitoneally injected with normal saline; the 5-Fu conventional dose group [5-Fu maximum tolerated dose (MTD) group], intraperitoneally injected with 50 mg/kg, twice per week for 2 weeks, with an 1-week discontinuation for 6 weeks; the capecitabine conventional dose group (capecitabine MTD group), intragastric 500 mg/kg, twice per week for 2 weeks, with a 1-week discontinuation for 6 weeks; the 5-Fu metronomic group [5-Fu low-dose metronomic (LDM) group], intraperitoneally injected with 15 mg/kg, twice a week for 6 weeks; and the capecitabine metronomic group (capecitabine LDM group), intragastric administration at 200 mg/kg, twice a week for 6 weeks. The chemotherapy resistance markers [glutathione transferase Pi (GSTP) and multidrug resistance protein 1 (MDR1)] were detected by immunohistochemical staining (IHC), and the association of the expression of these markers with the chemotherapy administration patterns was analyzed. Vascular endothelial growth factor (VEGF) and the cancer-associated fibroblast (CAF) marker α-smooth muscle actin were also examined by IHC to illustrate the possible mechanism of chemoresistance. The expression of GSTP and MDR1 in the MTD groups was significantly higher compared with those of the LDM groups (P<0.01). Furthermore, the number of CAFs and the level of VEGF in the MTD groups were significantly higher compared with those of the LDM groups (P<0.05). The low dose metronomic chemotherapy did not increase the risk of chemoresistance compared with the conventional dose traditional chemotherapy in terms of capecitabine or 5-Fu, the increasing amount of CAFs in the microenvironment of cancer cell following therapy may protect cell from capecitabine or 5-Fu via producing VEGF to increase vascularization.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Metronomic chemotherapy remodel cancer‑associated fibroblasts to decrease chemoresistance of gastric cancer in nude mice

Wang

Jiang

et al. 2017

Oncol Lett

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“…For instance, depleting stroma-derived WNT16B, which would specifically overcome such a "new" but not "minor" TME-associated resistance mechanism [57,60]. As supporting evidence, CAFs are similarly enriched in colorectal cancer (CRC) during the post-therapy stage and display enhanced cytokine IL-17A, which helps maintain the tumor infiltrating cells (TICs) through activation of NF-κB signaling [61].…”

Section: The Therapeutically Remodeled Tme Alters Clinical Outcomementioning

confidence: 98%

Updated Landscape of the Tumor Microenvironment and Targeting Strategies in an Era of Precision Medicine

Sun¹,

Chiao²

2017

Patient Centered Medicine

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Despite successive advances in clinical diagnosis and therapeutic intervention, cancerassociated morbidity and mortality keeps up with escalating cost to human society. Clinicians are confronted with an unprecedented challenge in curing cancers with de novo or acquired resistance. Failure to achieve effective and long-lasting treatment effects arises from the complexity of malignancies, particularly when plasticity of cancer cells is coupled with survival adaptability conferred by the pathologically co-opted stroma in the tumor microenvironment (TME). Targeting immune checkpoints, such as programmed cell death 1 (PD-1), programmed cell death ligand 1 (PD-L1) and cytotoxic T lymphocyte antigen 4 (CTLA4), provide significant benefit in multiple tumor types and produce substantial anticancer responses. Tissue resident stromal cells, although damaged together with cancer cells upon cytotoxic treatments, represent an everreplenishing source that contributes to tumor restoration from residual cancer cells in the post-therapy stage. The TME displays a continually changing landscape, generating significant impacts on treatment outcome in clinics. Moving forward, implementing patient-specific analysis in clinical oncology with TME-oriented agents will significantly improve the specificity and efficacy of targeted therapies, thereby accelerating the translation of novel conceptions and groundbreaking discoveries in the TME biology through multiple bench-to-bed pipelines in current settings of precision cancer medicine.

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“…It is quite established that cancer cells obeying to the operational definition of "stem cells" are highly resistant to conventional therapies, and thus are the most likely cause of tumor recurrence (30). In colorectal C-IC, chemoresistance has been associated with the activity of autocrine IL4 (37), or the paracrine stimulation by IL17A, a factor that promotes also self-renewal (38), or the activity of transcription factors ID1 and ID3, critical for sustaining the stem phenotype (32). Altogether, these data support the conclusion that "determinants of stemness" deeply contribute to therapeutic resistance (30) and enhance the interest in the stemness promoting activity of HGF as a cause of failure of conventional and targeted therapy.…”

Section: Colorectal Cancer Stem Cells: the Root Of The Tumor Resistanmentioning

confidence: 99%

MET-Mediated Resistance to EGFR Inhibitors: An Old Liaison Rooted in Colorectal Cancer Stem Cells

2014

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Inhibitors of EGFR are currently approved for the therapy of metastatic colorectal cancer (as well as other tumors), but their benefits are limited by inherent and acquired resistance, whose mechanisms are the subject of intense investigation. It is known that such resistance relies on a handful of genetic lesions and/or extracellular signals bypassing the requirement of EGF for cell proliferation and survival. As recently shown, these mechanisms may imply oncogenic activation of MET or its stimulation by the ligand hepatocyte growth factor. However, it is still largely obscure if sensitivity or resistance to EGFR inhibitors operates in cancer stem cells. Convincing evidence indicates that this elusive cell subpopulation is present at the roots of colorectal cancer. Conceivably, cancer stem cells accumulate the genetic lesions driving tumor onset and progression, as well as the genetic determinants of sensitivity or resistance to conventional and targeted therapies. Recent studies enlighten the expression of functional EGFR and MET in colorectal cancer stem cells and the outcome of their inhibition. Evidence is provided that, in patients sensitive to EGFR therapy, association of MET inhibitors fosters cancer stem cell eradication and durable tumor regression. Cancer Res; 74(14); 3647-51. Ó2014 AACR.

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Chemotherapy activates cancer-associated fibroblasts to maintain colorectal cancer-initiating cells by IL-17A

Abstract: Chemotherapy stimulates cancer-associated fibroblasts to secrete interleukin-17A to provide maintenance cues to support the growth of colorectal cancer-initiating cells.

Cited by 310 publications

References 98 publications

Metronomic chemotherapy remodel cancer‑associated fibroblasts to decrease chemoresistance of gastric cancer in nude mice

Metronomic chemotherapy remodel cancer‑associated fibroblasts to decrease chemoresistance of gastric cancer in nude mice

Updated Landscape of the Tumor Microenvironment and Targeting Strategies in an Era of Precision Medicine

MET-Mediated Resistance to EGFR Inhibitors: An Old Liaison Rooted in Colorectal Cancer Stem Cells

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