Year: 2017
Type: article
Abstract: The metastatic process is the main cause of cancer-associated death. Nonetheless, its underlying pathophysiological and molecular mechanisms are still poorly understood. The dissemination of malignant cells from the primary tumor to distant organs is a multistep process that requires detachment of cancer cells from the site of origin, remodeling of the extracellular matrix (ECM), migration into blood or lymph vessels, seeding to an ectopic tissue and proliferation. In recent years, tumor-infiltrating immune cells have been demonstrated to be critical determinants for ECM remodeling and metastatic progression. In particular, tumor-associated macrophages (TAMs) are able to suppress CD8+ T-cell infiltration and anti-tumor immunity in primary tumors and can promote angiogenesis and metastasis formation. Although the number of studies in support of the pro-metastatic role of TAMs is rapidly increasing, the molecular mechanisms through which these cells act are not completely elucidated. A gene-profiling analysis performed in our group on tumor-infiltrating myeloid cells from different murine tumors showed a significant upregulation of a specific pathway related to the endocytosis of plasma membrane receptors. In the present work, we prove that in TAMs the activation of this endocytic pathway is associated with an increased number of lung metastases in different murine tumor models. Our data show that the endocytic pathway is activated during the in vitro M- or GM-CSF–induced macrophage differentiation. Interestingly, in tissue slices from murine tumors and metastatic lungs, we found the up-regulation of the same pathway in TAMs localized along the invasion frontline between the tumor and the surrounding healthy tissues. The activation of the endocytic process in these TAMs induced the remodeling of the ECM and tumor cell invasiveness. Through a gene set enrichment analysis, we identified the transcriptional factor involved in the regulation of the pathway. We validated the regulation mechanism by means of gene silencing, substrate stiffness modulation and immunofluorescence. Finally, in biopsies from breast cancer patients, we found that the activation of this particular endocytic pathway correlated with a poor prognosis in terms of lymph node metastases, tumor vascularization, cancer cell proliferation and disease-free survival. The results achieved with this work allow us to propose a novel role for endocytosis in the macrophage-assisted metastatic process. Moreover, the identified pathway represents a new, potential prognostic marker for breast cancer patients.
Author: Kevin Leone
Language: English
Topic: Immune cells in cancer
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2778249290