Obesity is associated with an increased risk of developing breast cancer, and a greater probability for the cancer to spread to other organs – metastasize –. But the causes of this association are still not well understood. Researchers at the Spanish National Cancer Research Center (CNIO) have now provided new data by discovering that a high-fat diet activates mechanisms that facilitate metastasis.
This is a study led by Héctor Peinado, head of the CNIO's Microenvironment and Metastasis Group , conducted in animal models of triple-negative breast cancer that develop lung metastasis. It is published today in Nature Communications.
For cancer to spread to other organs, many tumor cells must leave the primary tumor, travel through the bloodstream, nest and proliferate in another organ. Sometimes the primary tumor sends molecules that modify the target organ in advance, and prepare the equivalent of a nest that hosts the tumor cells: this is the so-called 'premetastatic niche', in which the tumor cell can take root and develop metastases.
The CNIO group shows in their new study that mice which are obese from eating too much fat experience changes that favor the creation of the premetastatic niche, in this case in the lungs. Specifically, platelet activation and blood clotting capacity are increased; in addition, fibronectin, the protein that connects lung tissue cells, is activated.
A platelet armor
It is an established fact that obesity promotes blood clotting, a process that depends on blood cells called platelets. Indeed, as CNIO researcher and first author of the study Marta Hergueta observed, in animals fed with high fat, the cells that are shed from the primary tumor are surrounded, during their journey through the blood, by more platelets than in mice with a normal diet.
One hypothesis is that the platelets could be making it difficult for the body's defenses to detect the cancer cells: the platelets would form "an armor around the tumor cells, preventing the immune system from recognizing and eliminating them," explains Peinado.
Fertile breeding ground for metastasis
In addition to affecting platelets, the CNIO group found that the high-fat diet increases the expression of the protein fibronectin in the lung tissue where tumor cells metastasize.
Fibronectin builds the tissue that connects lung cells, thus facilitating the creation of the premetastatic niche that hosts the tumor cell. It also enables the tumor cell to interact more efficiently with platelets. "We have seen that the interaction of the tumor cell with both the lung endothelium and the platelet is regulated by fibronectin," says Peinado.
Studies in patients
To study the implications of these results for human patients, the CNIO's Breast Cancer Clinical Research Unit , directed by Miguel Ángel Quintela, participated in the study.
After analysing blood samples from triple-negative breast cancer patients, obtained before surgery and after undergoing chemotherapy, it could not be verified that obesity posed an additional risk for the generation of metastases. However, patients with increased blood coagulation – with a shorter prothrombin time – were found to have a higher risk of relapse at five years.
These findings "could help identify additional risk factors in breast cancer patients undergoing treatment, thus contributing to a better clinical management of the disease," says Peinado.
Potential clinical application
The work, carried out in collaboration with other CNIO units and other centres in Spain and Canada, has explored initial avenues for clinical application of the results. One of them was to modify the diet in animal models. When the high-fat diet was withdrawn, and the mice lost weight, platelet and coagulation behavior returned to normal levels. As a result, metastases were reduced.
"I think these results, coupled with clinical studies from other groups, present a future where dietary intervention or dietary changes, along with control of platelet activity, may increase the efficiency of certain antitumor treatments," Peinado says. "They are not going to be treatments by themselves, but they can complement them."
Funding
This study has been financed mainly by the British NGO Worldwide Cancer Research, in addition to state funds from the Ministry of Science and Innovation, the State Research Agency and the Carlos III Health Institute, as well as European ERDF funds and by private grants from the 'la Caixa' Foundation and the Spanish Association Against Cancer (AECC).
