Versican and Tumor-Associated Macrophages Promotes Tumor Progression and Metastasis in Canine and Murine Models of Breast Carcinoma.

Diego Carlos Dos Reis,Paula Peixoto Campos,Emerson Soares Veloso,Matheus Silvério Mattos,Gabriela Rafaela Arantes Pêgas,Dawidson Assis Gomes,Geovanni Dantas Cassali,Michele Angela Rodrigues,Remo Castro Russo,Enio Ferreira,Cecília Bonolo De Campos,Lucas Rocha Kraemer,Karine Araújo Damasceno

doi:10.3389/fonc.2019.00577

Abstract

Versican and tumor-associated macrophages (TAMs) are involved in growth and metastases in several cancers. Here, we investigated the potential role of versican, a matrix proteoglycan, and its correlation with TAMs infiltrates in different stages of two different breast cancer models: spontaneous canine mammary gland carcinomas and the murine 4T1 breast cancer model. The stromal versican expression was correlated with TAMs accumulation in tumors with an advanced stage from spontaneous canine mammary carcinoma samples. Versican expression in mice, identified in late stages of tumor progression, was associated to a high number of peri-tumoral infiltrating TAMs. Indeed, TAMs were related to a pro-inflammatory and pro-angiogenic state in the primary tumor. Furthermore, TAMs accumulation was related to versican expression in the lungs and an increased number of pulmonary metastatic nodules with pulmonary mechanical dysfunction, which was due to leukocyte influx in the airways and elevated growth factor levels in the microenvironment. Thus, we suggest that versican and TAMs as attractive targets for breast cancer therapy.

Highlights

The tumor microenvironment has been increasingly recognized as an important participant of tumor progression [1, 2] and metastasis [3]
Versican expression was observed in the stroma, myxoid matrix, and endothelial cells of blood vessels, inflammatory cells, and fibroblasts
Versican expression has been linked with poor prognosis and relapse-free survival in cancer patients [15, 41, 42]

Summary

Introduction

The tumor microenvironment has been increasingly recognized as an important participant of tumor progression [1, 2] and metastasis [3]. Interaction between ECM and Frontiers in Oncology | www.frontiersin.org dos Reis et al. Versican and TAMs Promotes Tumor inflammatory cells, mostly macrophages have been shown to be involved in the progression and development of breast cancer metastasis [7]. Lung metastasis may affect the pulmonary microenvironment and its function. Reduced lung function is an important risk factor for lung cancer, increasing the surgical risk of patients with advanced lung cancer, in which the low forced expiratory volume (FEV1) is strongly associated with mortality of non-small cell lung cancer patients [10]

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