Metronomic chemotherapy prevents therapy-induced stromal activation and induction of tumor-initiating cells

Tze Sian Chan, Chung Chi Hsu, Vincent C. Pai, Wen Ying Liao, Shenq Shyang Huang, Kok Tong Tan, Chia Jui Yen, Shu Ching Hsu, Wei Yu Chen, Yan Shen Shan, Chi Rong Li, Michael T. Lee, Kuan Ying Jiang, Jui Mei Chu, Gi Shih Lien, Valerie M. Weaver, Kelvin K. Tsai

Research output: Contribution to journalArticlepeer-review

58 Citations (Scopus)

Abstract

Although traditional chemotherapy kills a fraction of tumor cells, it also activates the stroma and can promote the growth and survival of residual cancer cells to foster tumor recurrence and metastasis. Accordingly, overcoming the host response induced by chemotherapy could substantially improve therapeutic outcome and patient survival. In this study, resistance to treatment and metastasis has been attributed to expansion of stem-like tumor-initiating cells (TICs). Molecular analysis of the tumor stroma in neoadjuvant chemotherapy-treated human desmoplastic cancers and orthotopic tumor xenografts revealed that traditional maximum-tolerated dose chemotherapy, regardless of the agents used, induces persistent STAT-1 and NF-κB activity in carcinoma-associated fibroblasts. This induction results in the expression and secretion of ELR motif-positive (ELR+) chemokines, which signal through CXCR-2 on carcinoma cells to trigger their phenotypic conversion into TICs and promote their invasive behaviors, leading to paradoxical tumor aggression after therapy. In contrast, the same overall dose administered as a low-dose metronomic chemotherapy regimen largely prevented therapy-induced stromal ELR+ chemokine paracrine signaling, thus enhancing treatment response and extending survival of mice carrying desmoplastic cancers. These experiments illustrate the importance of stroma in cancer therapy and how its impact on treatment resistance could be tempered by altering the dosing schedule of systemic chemotherapy.

Original languageEnglish
Pages (from-to)2967-2988
Number of pages22
JournalJournal of Experimental Medicine
Volume213
Issue number13
DOIs
Publication statusPublished - 2016 Dec 12

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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