Overall, tumor cells develop and grow surrounded by other non-tumor cells that form what is called the tumor stroma. This is made up of different cell types, especially fibroblasts and, to a lesser extent, different types of leukocytes (cells of inflammation) and blood vessels. The function of the stroma, when it is activated and its functional capacity increases, is to generate new blood vessels that allow the tumor cells to reach the nutrients and oxygen for their growth; in this way, the tumor grows and progresses.
It is important to note that activated stroma is not specific to cancer, but is the mechanism for growing all normal tissue, as occurs in wound healing. Both the proliferating cells of normal tissues and tumor cells in cancer send signals to their stroma so that it is activated and new blood vessels are generated that allow tissue growth. The difference is that in cancer the signals that tumor cells send to the stroma are continuous and the stroma is also continuously activated. Certainly, a classic work by Dr. Dvorak, published in the prestigious New England Journal of Medicine as early as 1986, proposed that tumors were “wounds that never complete healing.”
In the study recently published, in the Cancer Research journal by the groups of Jesús Pérez Losada of the Institute of Molecular and Cellular Biology of Cancer of Salamanca (IBMCC) and of Sonia Castillo Lluva, of the Complutense University of Madrid, it is shown that one of the essential genes for keeping the stroma fully active is the SNAI2 gene. In this study, in a mouse model that generates breast cancer, the authors show that the absence of SNAI2 in the tumor stroma makes it more difficult to activate and perform its function worse.
This translates into a greater difficulty for the tumor to grow, with less proliferation of tumor cells. Furthermore, if this stroma is subjected to functional stress (that is, it is “asked” to increase its function even more), which is achieved by increasing the oncogenic activity of tumor cells, then a defect is even observed in tumor metastasis. “Certainly,” Jesús Pérez Losada agrees, “SNAI2 had previously been related to tumor dissemination when it is active in the tumor cells themselves, but in this work it is shown that stromal insufficiency due to the loss of SNAI2 is also associated with a defect in tumor spread. All these results suggest that the inhibition of SNAI2 in the stroma could be a useful therapeutic target for the treatment of breast cancer ”.
From the most immediate practical point of view, the new study also shows that the increased expression of SNAI2 in the stroma of tumors of patients with breast cancer is associated with a poor prognosis in a subgroup of them, specifically, in the carriers of luminal B tumors that are both HER2-positive.
In this framework, it should be remembered that, globally, there are four large molecular groups of breast cancer (called intrinsic subtypes), according to the pattern of genes they express: luminal A, luminal B, enriched in HER2 and basal. Furthermore, HER2-positive tumors, which are those that overexpress this receptor, include those enriched in HER2, but also part of the luminal tumors are (in fact, up to a third of HER2-positive tumors are also luminal). This classification of breast tumors has very important practical implications, because depending on the intrinsic tumor subtype, a priori have a better or worse prognosis and require more or less aggressive treatment. This classification has been essential to allow in recent years a more personalized clinical practice in the treatment of breast cancer.
In this sense, -says Sonia Castillo Lluva- this study shows that patients with breast tumors that are both luminal B and HER2 positive can be divided into two groups, according to the degree of expression of the SNAI2 protein in the tumor stroma. Thus, tumor-bearing patients with high levels of SNAI2 in the stroma are associated with a worse evolution of the disease. This does not mean that the overexpression of SNAI2 in the stroma is not participating in the growth of other subtypes of breast cancer; but its overexpression seems to have the greatest impact on a clinical level, to the point of even affecting the evolution and prognosis of patients, is in carriers of this tumor subtype, luminal B and HER2 positive.
The work has been possible thanks to the collaboration with researchers from the Complutense University of Madrid, the San Carlos Institute of Health Research in Madrid, the Faculty of Medicine of the University of Salamanca (Department of Surgery), the Bioinformatics group of the IBMCC and of the Oncology and Pathology Services of the Salamanca University Hospital (IBSAL), the Juntendo University of Tokyo and the Maine Medical Center Research Institute of the USA.
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