An international team of researchers, with the participation of the University of Granada (UGR), has revealed new data on why breast cancer has a higher incidence and is more aggressive in obese people. The reason is that peritumoral fat (the fat around the tumor) facilitates the expansion and invasion of cancer stem cells (CSCs), which are responsible of the onset and growth of the tumor.
CSCs are found in tumors in a very small proportion, and their main characteristic is that they are responsible of metastasis originating in parts of the body far from the original tumor. Conventional chemotherapy and radiotherapy treatments are not capable of eliminating said CSCs, and for that, it's very common that, after the first response to the treatment, many cancer patients suffer a relapse.
This new research work has been lead by the University of Miami (Florida, United States), and it has counted with the participation of researchers from Granada's University Hospital Center and from the UGR "Terapias avanzadas: diferenciación, regeneración y cáncer" (Advanced therapies: differentiation, regeneration and cancer) research team. Both groups of researchers belong to the Biosanitary Institute of Granada (ibs. GRANADA).
Mechanisms yet to be clarified
The consequences of the obesity epidemic on cancer morbidity and mortality are very serious. In fact, it is estimated that, nowadays, up to 20% of cancer-related deaths may be attributable to obesity.
Obese women have a greater risk of suffering breast cancer after menopause, and they have a worse progression of the disease no matter their age, but the mechanisms by which obesity contributes to the development and progression of cancer aren't clear yet. Obesity-related fat causes local inflammation and prevents adipocytes (the cells forming said fat) from maturing.
For this research, carried out in mice and published in the renowned Cancer Research journal, researchers assessed the effects of coculturing adipocytes with breast cancer cells on tumor aggressivity, capacity of local invasion and metastatic potential of said tumor.
The results show that the interaction between tumor cells and immature adipocytes near the tumor during the first stages of breast cancer increased the secretion of cytokines (proinflammatory proteins).
"Said cytokines cause a greater expansion of highly metastatic CSCs", UGR professor Juan Antonio Marchal Corrales, one of the authors of this paper, explains.
In addition, the researchers have described the mechanism by which this process takes place and its relation with the activation of the SRC Kinase protein. In turn, said protein induces the activation of the Sox2 transcription factor (essential to maintain stem cells characteristics) and of a small RNA molecule called miRNA-302b.
"The prolonged coculture of tumor cells with immature adipocytes or cytokines increased the proportion of CSCs (which had the ability to form new tumors), the presence of tumor cells in blood, and the metastatic potential after its implementation in mice" Marchal says. And last, we found that SRC-Kinase-inhibiting drugs decrease the production of cytokines and CSCs".
These findings reveal new insights underlying increased breast cancer mortality in obese individuals and provide a novel preclinical rationale to test the efficacy of SRC inhibitors for breast cancer treatment.