Metastasis marker

The appearance of metastasis contributes fundamentally to vascular endothelial growth factor A, produced by positive stromal cells for the S100A4 marker according to a new study carried out by Brazilian and North Americans.

By Fábio de Castro

Agência FAPESP – The appearance of metastasis contributes fundamentally to Vascular endothelial growth factor A (VEGF-A), produced by positive stromal cells for the S100A4 marker according to a new study carried out by Brazilian and North Americans. The stroma is the connective tissue that sustains the functional cells in the organs.

According to the authors, the study published in Proceedings of the National Academy of Sciences magazine may have important clinical impact since patients testing positive for the s100A4 marker in cells—in theory more inclined to evidence metastasis—could be identified and benefit from existing anti-VEGF drugs.

The study had the participation of Ricardo Renzo Brentani and Rafael Meligoli Rocha, from Hospital A.C. Camargo’s Department of Oncology. Brentani is chief executive of FAPESP. The other authors are from North American institutions: Harvard Medical School, Pathology Department at Rhode Island Hospital, Vanderbuilt University in Nashville and the Harvard-MIT Health Sciences and Technology Division. VEGF-A promotes angiogenesis—the growth of new blood vessels—around the tumor. These vessels feed the tumor and at the same time facilitate metastasis.

“We found that VEGF-A appeared in stromal cells—which are basically fibroblasts—that compose the intracellular matrix. Because of this, they play a central role in metastatic colonization. But the most important thing is that the fibroblasts responsible for the production of VEGF-A could be positive for the S100A4 marker,” Rocha told Agência FAPESP.

According to him, there are drugs that block the action of VEGF, such as Bevacizumab, which was successful in the treatment of patients with metastatic disease, increasing survival rates. “We imagine that the patients with S100A4 in the stroma could benefit from anti-VEGF therapy,” he affirmed.
 
Rocha and Brentani established a partnership with the group led by Radhu Kalluri from Beth Israel Deaconess Medical Center, Harvard Medical School’s hospital. The study was published in PNAS and is the result of this partnership.

The experimental part of the study took place at Harvard, in two groups of mice: one group of transgenic animals that do not express the S100A4 protein and a control group able to express it. “This way, we were able to observe the differences between the two groups in VGEF production as well as the appearance of veins and metastases,” said Rocha.

In the Anatomic Pathology Laboratory of the Hospital A.C. Camargo, the scientists did the in situ molecular part of the study, performing immunohistochemical tests to identify the quantity of the S100A4 protein expressed in the stromal fibroblasts.

“From that point on, we could predict which patients would produce more vessels and be more susceptible to metastasis if they weren’t treated,” affirmed the scientist. According to Rocha, the study showed that the fibroblasts positive for S100A4 play a crucial role in the task of providing “fertile ground” for metastatic colonization, which according to him is a fundamental step in the metastatic cascade.

The article VEGF-A and Tenascin-C produced by S100A4+ stromal cells are important for metastatic colonization (doi/10.1073/pnas.1109493108), by Radhu Kalluri and others can be read PNAS subscribers at www.pnas.org/cgi/doi/10.1073/pnas.1109493108.