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

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.

• Authors: 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
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 213 Issue 13 Pg. 2967-2988 (12 12 2016) ISSN: 1540-9538 [Electronic] United States
• PMID: 27881732 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, N.I.H., Extramural)
• Copyright: © 2016 Chan et al.

Chemical References

• NF-kappa B
• Receptors, Interleukin-8B
• STAT1 Transcription Factor
• STAT1 protein, human

Topics

• Administration, Metronomic
• Breast Neoplasms (drug therapy, metabolism, pathology)
• Female
• Fibroblasts (metabolism, pathology)
• Humans
• MCF-7 Cells
• NF-kappa B (metabolism)
• Receptors, Interleukin-8B (metabolism)
• STAT1 Transcription Factor (metabolism)
• Stromal Cells (metabolism, pathology)
• U937 Cells