Changes in the structure of the skin and the lymphatic system that occur with the natural aging process, create a favorable environment for metastatic melanoma, according to two studies Wistar Institute. These changes are caused by the loss of HAPLN1 protein that is part of the extracellular matrix during aging. The studies were published in «Cancer Discovery».
Old age is a negative prognostic factor for melanoma associated with a higher incidence of incurable metastases. Researchers are paying a lot of attention to how aging affects the microenvironment of a melanoma tumor or the ecosystem, which includes immune cells, fibroblasts, blood and lymph vessels, and signaling molecules to understand how age-related changes contribute to tumor progression and treatment resistance.
In this new research, scientists described the architectural changes taking place in the extracellular matrix (ECM) of the skin and the surrounding lymph vessels that contribute to the spread of melanoma cells to distant sites by acting on tumor cell and immune cell trafficking. They also found a fundamental role HAPLN1 protein in the molecular mechanisms that underlie these changes.
In one study, researchers have focused on the ECM, produced by fibroblasts in the dermal layer of the skin, and a sharp change expression levels of many ECM proteins, particularly HAPLN1.
"The same structural changes that occur in our skin aging and cause the appearance of wrinkles, are also responsible for an increased risk of metastasis in melanoma patients' - Vereratna said senior author of both studies. "With age, the fiber network that supports our skin loses its organization 'weave baskets", which is characteristic of a more youthful skin and become more free. In the context of the tumor, we see it as a barrier that helps keep tumor cells by inhibiting their mobility, while at the same time contributing to the penetration of immune cells into the tumor mass. In elderly patients, due to the loss HAPLN1 this barrier becomes less effective. "
By manipulating HAPLN1 expression levels in the three-dimensional model of human skin reconstruction and in mouse skin models, researchers have shown that HAPLN1 loss creates resolution microenvironment that facilitates escape of tumor cells by inhibiting the anti-tumor immune cell trafficking, in particular CD8 + T-cells, Accordingly, the injection of recombinant HAPLN1 around tumor models in mouse melanoma and reduces the size of metastatic capacity of the tumor.
The second study shows that the age-related loss of lymphatic vessels integrity allows easier melanoma cells to accelerate the lymphatic system and proximal lymph nodes to reach remote areas. The results showed that this process is also associated with loss of HAPLN1, which leads to a similar scenario to that described in the skin: the degradation of the extracellular matrix, which are integrated in the lymph vessels and lymph reduced attachment of endothelial cells to their structural support, resulting in increased permeability.
"We know that older people with melanoma observed a lower rate of lymphatic metastasis than in younger patients, but higher rates of distant visceral metastases. Our observation that older lymph vessels and lymph nodes are less effective as a barrier to contain metastatic cells may underlie this observation. "
In this case, injection of recombinant HAPLN1 to drain the lymph nodes in elderly melanoma bearing mice increased the rate of lymphatic micrometastasis while reducing metastasis frequency in the lungs, indicating that the retention of metastatic cells in the local lymphatic system may have therapeutic implications when combined with surgical resection of the sentinel lymph node.
Taken together, these two studies support the new fundamental role HAPLN1 as a prognostic factor for long-term survival and potential new therapeutic method.