Inflammation promotes tumor aggression by stimulating stromal cell-dependent collagen crosslinking and stromal stiffening
| Autor: | Valerie M. Weaver, E. S. Hwang, Aastha Chauhan, Brian Ruffell, Jonathan N. Lakins, Lisa M. Coussens, O. Maller, P. T. Thanh, Zena Werb, Peter Kabos, Travis Nemkov, Alexander S. Barrett, Tina Gruosso, Allison P. Drain, Olöf Bjarnadottir, Hellen Kuasne, Jessica Gruenberg, Andrew C. Nelson, Irene Acerbi, Morag Park, J. M. Barnes, Kirk C. Hansen, Signe Borgquist, Aqsa Nasir |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0303 health sciences
Stromal cell biology Chemistry Lysyl hydroxylase technology industry and agriculture Lysyl oxidase macromolecular substances medicine.disease 3. Good health Metastasis Extracellular matrix 03 medical and health sciences Hydroxylysine chemistry.chemical_compound 0302 clinical medicine medicine.anatomical_structure Stroma 030220 oncology & carcinogenesis cardiovascular system Cancer research biology.protein medicine Fibroblast 030304 developmental biology |
| Popis: | Collagen deposition and stromal stiffening accompany malignancy, compromise treatment, and promote tumor aggression. Clarifying the molecular nature of and the factors that regulate extracellular matrix stiffening in tumors should identify biomarkers to stratify patients for therapy and therapeutic interventions to improve outcome. We profiled lysyl hydroxylase- and lysyl oxidase-mediated collagen crosslinks and quantified the greatest abundance of total and complex collagen crosslinks in more aggressive human breast cancer subtypes with the stiffest stroma. These tissues also harbored the highest number of tumor-associated macrophages (TAM), whose therapeutic ablation not only reduced metastasis, but also concomitantly decreased accumulation of collagen crosslinks and stromal stiffening. Epithelial-targeted expression of the crosslinking enzyme lysyl oxidase had no impact on collagen crosslinking in PyMT mammary tumors, whereas stromal cell targeting did. Consistently, stromal cells in microdissected human tumors expressed the highest level of collagen crosslinking enzymes. Immunohistochemical analysis of a cohort of breast cancer patient biopsies revealed that stromal expression of lysyl hydroxylase two, an enzyme that induces hydroxylysine aldehyde-derived collagen crosslinks and stromal stiffening correlated significantly disease specific mortality. The findings link tissue inflammation, stromal cell-mediated collagen crosslinking and stiffening to tumor aggression and identify lysyl hydroxylase two as a novel stromal biomarker.SignificanceWe show infiltrating macrophages induce stromal fibroblast, and not epithelial, expression of collagen crosslinking enzymes that drive tumor stiffening. Stromal enzyme LH2 is significantly upregulated in breast cancer patients with the stiffest stroma, the most trivalent HLCCs and the worst prognosis, underscoring its potential as a biomarker and therapeutic target. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|