The action of a protein, the B1 receptor of the hormone bradykinin, may be important to the development of less severe forms of melanoma, a very aggressive type of skin cancer, because of the high risk of its spreading to other parts of the body. Researchers from São Paulo and France have succeeded in inducing the disease in two groups of mice that were genetically altered to exclude this receptor; the mice presented more malignant tumors, and the metastasis was more widespread. In normal mice, which retained the functional B1, the skin cancer was less severe and more able to be controlled. “The presence of the B1 receptor appears to improve the body’s immune response to melanoma progression,” says biochemist Claudio Miguel Costa-Neto, of the University of São Paulo Ribeirão Preto School of Medicine (FMRP-USP), the lead author of the study, published in the February 2016 issue of the journal Scientific Reports.
The bradykinin receptors (in addition to B1, there is also a B2) are part of the kallikrein-kinin system, which is important for the regulation of a number of processes in the body, such as vasodilation, inflammatory response and pain sensation. This system can be modulated through the use of drugs. The relationship of the receptors to cancer development is still not well established. In the case of B2, existing studies suggest that it may promote the development of some tumors, such as prostate and lung tumors. “There is a possibility that B2 increases in transgenic mice that do not produce B1, but we did not evaluate the amount of that second receptor,” notes molecular biologist João Bosco Pesquero, of the Federal University of São Paulo (Unifesp), a co-author of the study and responsible for producing the genetically modified mice.
The possible role of B1 in tumors has been the subject of less research than that of B2. But, according to the new study, its presence in the body may protect against melanoma development. Only 10% of the tumors of the mice that retained the functional version of the receptor showed ulceration, indicative of the aggressiveness of the tumor. This rate was 50% in the transgenic mice. The presence of large colonies of lung metastases was three times higher in the mice without the protein than in the control group.
The next step in the research, part of a thematic project funded by FAPESP, is to test the action of compounds designed to stimulate B1 activation. There is always the risk that this strategy, while beneficial to controlling the skin cancer, will also produce unexpected damage. “We can now, however, create compounds capable of binding in receptors in a selective and specific way,” says Costa-Neto. “So we could, in theory, minimize possible side effects.”
Development of new ligands/drugs with selective agonistic action (biased agonism) for recipients of the renin-angiotensin and kallikrein-kinin systems: new properties and new biotechnological applications (nº 2012/20148-0); Grant Mechanism Thematic Project; Principal Investigator Claudio Miguel da Costa Neto (FMRP-USP); Investment R$ 1,893,525.25.
MARIA, A.G. et al. Host kinin B1 receptor plays a protective role against melanoma progression. Scientific Reports. February 22, 2016.