title: Paclitaxel therapy promotes breast cancer metastasis in a TLR4-dependent manner.
abstract: Emerging evidence suggests that cytotoxic therapy may actually promote drug resistance and metastasis while inhibiting the growth of primary tumors. Work in preclinical models of breast cancer has shown that acquired chemoresistance to the widely used drug paclitaxel can be mediated by activation of the Toll-like receptor TLR4 in cancer cells. In this study, we determined the prometastatic effects of tumor-expressed TLR4 and paclitaxel therapy and investigated the mechanisms mediating these effects. While paclitaxel treatment was largely efficacious in inhibiting TLR4-negative tumors, it significantly increased the incidence and burden of pulmonary and lymphatic metastasis by TLR4-positive tumors. TLR4 activation by paclitaxel strongly increased the expression of inflammatory mediators, not only locally in the primary tumor microenvironment but also systemically in the blood, lymph nodes, spleen, bone marrow, and lungs. These proinflammatory changes promoted the outgrowth of Ly6C(+) and Ly6G(+) myeloid progenitor cells and their mobilization to tumors, where they increased blood vessel formation but not invasion of these vessels. In contrast, paclitaxel-mediated activation of TLR4-positive tumors induced de novo generation of deep intratumoral lymphatic vessels that were highly permissive to invasion by malignant cells. These results suggest that paclitaxel therapy of patients with TLR4-expressing tumors may activate systemic inflammatory circuits that promote angiogenesis, lymphangiogenesis, and metastasis, both at local sites and premetastatic niches where invasion occurs in distal organs. Taken together, our findings suggest that efforts to target TLR4 on tumor cells may simultaneously quell local and systemic inflammatory pathways that promote malignant progression, with implications for how to prevent tumor recurrence and the establishment of metastatic lesions, either during chemotherapy or after it is completed.
authors.affiliation: Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine, Springfield, Illinois.
authors.forename: Lisa
authors.initials: L
authors.lastname: Volk-Draper
authors.affiliation: Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine, Springfield, Illinois.
authors.forename: Kelly
authors.initials: K
authors.lastname: Hall
authors.affiliation: Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine, Springfield, Illinois.
authors.forename: Caitlin
authors.initials: C
authors.lastname: Griggs
authors.affiliation: Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine, Springfield, Illinois.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Rajput
authors.affiliation: Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine, Springfield, Illinois.
authors.forename: Pascaline
authors.initials: P
authors.lastname: Kohio
authors.affiliation: Department of Medicine, Oncology Division, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: David
authors.initials: D
authors.lastname: DeNardo
authors.affiliation: Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine, Springfield, Illinois. sran@siumed.edu.
authors.forename: Sophia
authors.initials: S
authors.lastname: Ran
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007249:Inflammation / Q000139:chemically induced; D009362:Neoplasm Metastasis; D017239:Paclitaxel / Q000627:therapeutic use*; D051197:Toll-Like Receptor 4 / Q000502:physiology*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D017239:Paclitaxel