T Cells Promote Metastasis by Regulating Extracellular Matrix Remodeling following Chemotherapy
Autor: | Mahesh Devarasetty, Yuval Shaked, Tim J Cooper, Michael Timaner, Shay Soker, Avital Vorontsova, Tamar Barenholz-Cohen, Ruth Scherz-Shouval, Oshrat Levi-Galibov, Daphne Weihs, Jozafina Haj-Shomaly, Ziv Raviv, Peleg Hasson |
---|---|
Rok vydání: | 2021 |
Předmět: |
Cancer Research
Adoptive cell transfer Lung Neoplasms Paclitaxel Breast Neoplasms Lysyl oxidase Mice SCID CD8-Positive T-Lymphocytes Metastasis Protein-Lysine 6-Oxidase Extracellular matrix Mice 03 medical and health sciences 0302 clinical medicine Immune system medicine Animals Humans 030304 developmental biology Mice Knockout Extracellular Matrix Proteins Mice Inbred BALB C 0303 health sciences Chemistry Mammary Neoplasms Experimental Cancer medicine.disease Adoptive Transfer Antineoplastic Agents Phytogenic Extracellular Matrix 3. Good health Oncology 030220 oncology & carcinogenesis Cancer cell MCF-7 Cells Cancer research Female CD8 |
Zdroj: | Cancer Research. 82:278-291 |
ISSN: | 1538-7445 0008-5472 |
Popis: | Metastasis is the main cause of cancer-related mortality. Despite intense efforts to understand the mechanisms underlying the metastatic process, treatment of metastatic cancer is still challenging. Here we describe a chemotherapy-induced, host-mediated mechanism that promotes remodeling of the extracellular matrix (ECM), ultimately facilitating cancer cell seeding and metastasis. Paclitaxel (PTX) chemotherapy enhanced rapid ECM remodeling and mechanostructural changes in the lungs of tumor-free mice, and the protein expression and activity of the ECM remodeling enzyme lysyl oxidase (LOX) increased in response to PTX. A chimeric mouse model harboring genetic LOX depletion revealed chemotherapy-induced ECM remodeling was mediated by CD8+ T cells expressing LOX. Consistently, adoptive transfer of CD8+ T cells, but not CD4+ T cells or B cells, from PTX-treated mice to naïve immunodeprived mice induced pulmonary ECM remodeling. Lastly, in a clinically relevant metastatic breast carcinoma model, LOX inhibition counteracted the metastasis-promoting, ECM-related effects of PTX. This study highlights the role of immune cells in regulating ECM and metastasis following chemotherapy, suggesting that inhibiting chemotherapy-induced ECM remodeling represents a potential therapeutic strategy for metastatic cancer. Significance: Chemotherapy induces prometastatic pulmonary ECM remodeling by upregulating LOX in T cells, which can be targeted with LOX inhibitors to suppress metastasis. See related commentary by Kolonin and Woodward, p. 197 |
Databáze: | OpenAIRE |
Externí odkaz: |