Breast cancer affects more obese women because fat facilitates the expansion of cancer stem cells

January 19, 2016

Photo: Tony Alter (FLICKR)

The results have been published in the latest issue of the prestigious journal Cancer Research

An international team of scientists, in which the University of Granada participates, has provided new data on why breast cancer affects more and is more aggressive towards obese people. The reason is that the peritumoral fat, that is, the fat that surrounds the tumor, facilitates the expansion and invasion of cancer stem cells (CMCs), responsible for the initiation and growth of cancer.

CMCs are found in tumors in very low numbers, and their important characteristic is the formation of metastases at sites other than the original tumor. Conventional chemotherapy and radiotherapy are not capable of destroying these CMCs, so that on many occasions, after an initial response to treatment, many cancer patients have relapses because these CMCs have not been destroyed.

This new research work has been led by the University of Miami (United States), and involved scientists from the Granada University Hospital Complex and the research group "Advanced Therapies: differentiation, regeneration and cancer" from the University of Granada ( UGR), also belonging to the Biosanitary Research Institute of Granada (ibs.GRANADA).

Some mechanisms still unclear

The consequences of the obesity epidemic on cancer morbidity and mortality are very serious. In fact, it is estimated that up to 20 percent of cancer deaths today may be attributable to obesity.

Obese women have an increased risk of breast cancer after menopause and worse course of the disease at any age, but the mechanisms by which it contributes to the development of cancer and the evolution of patients are not yet clear.
Fat in obesity leads to local inflammation and the non-maturation of the cells that make up this fat, adipocytes.

In this study in mice, published in the latest issue of the prestigious journal Cancer Research, scientists examined the effects of co-culturing fat cells (adipocytes) and breast cancer cells, both obtained from the same patients, on tumor aggressiveness, local invasiveness, and tumor metastasis.

The results indicate that the interaction that occurs early in the invasion of breast cancer, between tumor cells and immature adipocytes close to the tumor, induces an increased secretion of cytokines or pro-inflammatory proteins.

"These cytokines give rise to a greater expansion of highly metastatic cancer stem cells (CMCs)", explains the UGR professor. Juan Antonio Marchal Corrales, one of the authors of this work.

Preclinical evidence

In addition, researchers have described the mechanism by which this process takes place, and that it is related to the activation of the SRC protein kinase, which in turn induces the activation of the transcription factor Sox2, which is essential for the maintenance of the characteristics of stem cells, and of a small RNA molecule called microRNA-302b (miRNA-302b).

"Prolonged culture of tumor cells with immature adipocytes, or with these cytokines, increased the proportion of CMCs, which had an ability to form new tumors, an increase in circulating tumor cells in the blood and a greater metastatic potential after implantation in mice Marchal points out. Finally, we found that inhibitors of the SRC protein kinase decrease the production of cytokines and CMCs.

These findings reveal new insights underlying the increase in breast cancer mortality in obese women, and provide preclinical evidence to test the efficacy of SRC protein kinase inhibitor drugs in the treatment of breast cancer.

Bibliographic reference:

interactions between
Adipocytes and Breast Cancer Cells Stimulate Cytokine Production and Drive

Src / Sox2 / miR-302b – Mediated Malignant Progression

Manuel Picon-Ruiz, Chendong Pan, Katherine
Drews-Elger, Kibeom Jang, Alexandra H. Besser, Dekuang Zhao, Cynthia

Morata-Tarifa, Minsoon Kim, Tan A. Ince, Diana J. Azzam, Seth A. Wander, Bin

Wang, Burcu Ergonul, Ram H. Datar, Richard J. Cote, Guy A. Howard, Dorraya

El-Ashry, Pablo Torne-Poyatos, Juan A. Marchal, and Joyce M. Slingerland

Cancer Research 2016 Jan 15; 76 (2): 491-504.

DOI: 10.1158/0008-5472.CAN-15-0927

The full article is available at the following link:

http://cancerres.aacrjournals.org/content/early/2016/01/07/0008-5472.CAN-15-0927.long

Contact:
Juan Antonio Marchal Corrales