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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Oncol. | doi: 10.3389/fonc.2019.00685

4T1 mammary carcinoma colonization of metastatic niches is accelerated by obesity

  • 1University of São Paulo, Brazil
  • 2Universidade Federal de Juiz de Fora, Brazil
  • 3Instituto do Câncer do Estado de São Paulo, Brazil
  • 4Laboratory of Experimental Oncology, Instituto do Câncer do Estado de São Paulo, Brazil
  • 5Brazilian National Cancer Institute (INCA), Brazil

Breast cancer (BC) remains the leading cause of cancer-related deaths among women, and the chances to develop it are duplicated by obesity. Still, the impact of obesity in BC progression remains less understood. We investigated the role of obesity in tumor progression using the murine model of 4T1 mammary carcinoma in BALB/c female mice, previously high-fat-diet (HFD) fed. HFD induced obesity, metabolic impairment, and high serum and fat leptin levels. After injection of 4T1-cells, HFD-mice accelerated tumor progression and metastasis. 4T1-cells found within HFD-mice metastatic niches presented higher clonogenic potential. 4T1-cells treated in vitro with fat-conditioned medium derived from HFD-mice, increased migration capacity through CXCL12 and CCL25 gradients. In HFD-mice, the infiltration and activation of immune cells into tumor-sentinel lymph nodes was overall reduced, except for activated CD4+ T cells expressing low CD25 levels. Within the bone marrow, the levels of haematopoiesis-related IL-6 and TNF-α after 4T1-cells injection decreased in HFD-mice whereas increased in the controls, suggesting that upregulation of both cytokines, regardless of the tumor, is disrupted by obesity. Finally, the expression of genes for leptin, CXCR4, and CCR9 (receptors of CXCL12 and CCL25, respectively) was negatively correlated with the infiltration of CD8 T cells in human triple-negative BC tumors from obese patients compared to non-obese. Together, our data presented early evidence of systemic networks triggered by obesity that promote BC progression to the metastatic niches, which might be targeted to prevent the accelerated BC progression among obese patients.

Keywords: Obesity, breast cancer, 4T1 cells, High fat diet (HFD), Immune-cells infiltration

Received: 02 Apr 2019; Accepted: 11 Jul 2019.

Edited by:

Jose A. Garcia-Sanz, Spanish National Research Council (CSIC), Spain

Reviewed by:

Fabiana Napolitano, School of Medicine and Surgery, University of Naples Federico II, Italy
Tomohiro Chiba, Kyorin University School of Medicine, Japan  

Copyright: © 2019 Evangelista, Salvador, Clavijo-Salomón, Soares, Barros, Xavier, Abdo, Gualberto, Macedo and Gameiro. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Mx. Gabriela Coeli M. Evangelista, University of São Paulo, São Paulo, Brazil, gabrielacoeli@usp.br