title: 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.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.|Laboratory of Advanced Molecular Therapeutics, Division of Gastroenterology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 11031, Taiwan.
authors.forename: Tze-Sian
authors.initials: TS
authors.lastname: Chan
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.|Laboratory for Tumor Aggressiveness and Stemness, National Institute of Cancer Research, National Health Research Institutes, Tainan City 70456, Taiwan.
authors.forename: Chung-Chi
authors.identifier: 0000-0001-7474-7578
authors.initials: CC
authors.lastname: Hsu
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.|Laboratory for Tumor Aggressiveness and Stemness, National Institute of Cancer Research, National Health Research Institutes, Tainan City 70456, Taiwan.
authors.forename: Vincent C
authors.initials: VC
authors.lastname: Pai
authors.affiliation: Laboratory for Tumor Aggressiveness and Stemness, National Institute of Cancer Research, National Health Research Institutes, Tainan City 70456, Taiwan.
authors.forename: Wen-Ying
authors.identifier: 0000-0002-3266-7294
authors.initials: WY
authors.lastname: Liao
authors.affiliation: Graduate Program of Biotechnology in Medicine, Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu 30013, Taiwan.
authors.forename: Shenq-Shyang
authors.identifier: 0000-0001-8476-3141
authors.initials: SS
authors.lastname: Huang
authors.affiliation: Department of Surgery, Tung's Metro-harbor Hospital, Taichung 43503, Taiwan.
authors.forename: Kok-Tong
authors.initials: KT
authors.lastname: Tan
authors.affiliation: Division of Hematology and Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan 70403, Taiwan.
authors.forename: Chia-Jui
authors.initials: CJ
authors.lastname: Yen
authors.affiliation: National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Tainan City 70456, Taiwan.
authors.forename: Shu-Ching
authors.initials: SC
authors.lastname: Hsu
authors.affiliation: Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei 11031, Taiwan.
authors.forename: Wei-Yu
authors.initials: WY
authors.lastname: Chen
authors.affiliation: Department of Surgery, National Cheng Kung University Hospital, Tainan 70403, Taiwan.
authors.forename: Yan-Shen
authors.initials: YS
authors.lastname: Shan
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
authors.forename: Chi-Rong
authors.identifier: 0000-0002-0314-8284
authors.initials: CR
authors.lastname: Li
authors.affiliation: Department of Computer Science, Kun Shan University, Tainan 71003, Taiwan.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Lee
authors.affiliation: Laboratory for Tumor Aggressiveness and Stemness, National Institute of Cancer Research, National Health Research Institutes, Tainan City 70456, Taiwan.
authors.forename: Kuan-Ying
authors.identifier: 0000-0002-7806-5475
authors.initials: KY
authors.lastname: Jiang
authors.affiliation: Laboratory for Tumor Aggressiveness and Stemness, National Institute of Cancer Research, National Health Research Institutes, Tainan City 70456, Taiwan.
authors.forename: Jui-Mei
authors.initials: JM
authors.lastname: Chu
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.|Laboratory of Advanced Molecular Therapeutics, Division of Gastroenterology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 11031, Taiwan.
authors.forename: Gi-Shih
authors.identifier: 0000-0003-1135-339X
authors.initials: GS
authors.lastname: Lien
authors.affiliation: Department of Surgery, Center for Bioengineering and Tissue Regeneration, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143.|Department of Anatomy, Center for Bioengineering and Tissue Regeneration, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143.|Department of Bioengineering and Therapeutic Sciences, Center for Bioengineering and Tissue Regeneration, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143.
authors.forename: Valerie M
authors.identifier: 0000-0003-4786-6752
authors.initials: VM
authors.lastname: Weaver
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan tsaik@tmu.edu.tw tsaik@nhri.org.tw.|Laboratory for Tumor Aggressiveness and Stemness, National Institute of Cancer Research, National Health Research Institutes, Tainan City 70456, Taiwan.|Division of Hematology and Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan 70403, Taiwan.
authors.forename: Kelvin K
authors.identifier: 0000-0002-7957-3914
authors.initials: KK
authors.lastname: Tsai
mesh_terms: D059250:Administration, Metronomic; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006801:Humans; D061986:MCF-7 Cells; D016328:NF-kappa B / Q000378:metabolism*; D023063:Receptors, Interleukin-8B / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D020298:U937 Cells
chemical_list: D016328:NF-kappa B; D023063:Receptors, Interleukin-8B; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human