Scientists at HSE University have identified a molecular mechanism underlying aggressive breast cancer. They found that the signals supporting tumour growth originate not from the tumour itself but from its microenvironment. The researchers also demonstrated that reduced levels of the IGFBP6 protein in the tumour microenvironment lead to the accumulation of macrophages—immune cells associated with a higher risk of cancer recurrence. These findings already make it possible to assess patient risk more accurately and may, in the future, enable the development of drugs that target cells of the tumour microenvironment. The study has been published in Current Drug Therapy.
Triple-negative breast cancer is an aggressive type of tumour that accounts for about 20% of breast cancer cases . It is named for the absence of three receptors that usually serve as targets for therapy: estrogen, progesterone, and human epidermal growth factor receptors. This type of cancer occurs more frequently in younger women, metastasises faster than other forms, and is associated with a high risk of recurrence.
Because it lacks well-established drug targets, this type of cancer is particularly difficult to treat. As a result, researchers study not only the cancer cells themselves but also their surroundings, including connective tissue, immune cells, and blood vessels. Together, these components form the tumour microenvironment, which can either restrain tumour growth or, conversely, promote it.
A team of researchers from the HSE Faculty of Biology and Biotechnology has identified features of the tumour microenvironment that are associated with a more aggressive course of cancer and a higher risk of early recurrence. To do this, they analysed gene activity in both tumour cells and their surrounding microenvironment and compared this data with patients' clinical records. The researchers paid particular attention to the IGF2 gene, which encodes insulin-like growth factor 2 (IGF2). Under normal conditions, IGF2 is a signalling protein involved in tissue growth and repair, but in cancer it begins to stimulate tumour cell proliferation.
The researchers found that the main supplier of 'fuel' for tumour growth—the IGF2 protein—is not the cancer cells themselves but fibroblasts, connective tissue cells that are part of the tumour microenvironment. Under normal conditions, fibroblasts support tissue structure, but in disease they can instead promote tumour development. At the same time, the tumour also has a built-in containment system. The regulatory protein IGFBP6 acts as a trap for IGF2, preventing it from uncontrollably stimulating tumour growth. The researchers found that IGFBP6 is produced by both microenvironmental cells and the tumour cells themselves in an attempt to maintain growth in balance.
The link between this mechanism and the clinical course of the disease became apparent during the analysis of patient data. Lower levels of IGFBP6 in tumours were associated with increased infiltration by macrophages—immune cells that normally protect the body but, in established tumours, can 'switch sides' and begin to support cancer cells, leading to earlier disease recurrence.
Even now, these results can be used to more accurately assess risk and guide patient monitoring: those with a higher likelihood of early recurrence may benefit from more intensive monitoring and treatment. In the long term, these findings could inform the development of targeted therapies aimed at the tumour microenvironment.
'Conventional chemotherapy primarily targets rapidly dividing cells, and in triple-negative breast cancer this is often insufficient. We propose shifting the focus to the tumour microenvironment and targeting the cells that support tumour growth,' comments Maxim Shkurnikov, Head of the Laboratory for Research on Molecular Mechanisms of Longevity at the HSE Faculty of Biology and Biotechnology and co-author of the article. 'For example, one could aim to artificially increase IGFBP6 levels or inhibit IGF2 production by fibroblasts. This approach could deprive the tumour of critical support and reduce the risk of rapid recurrence.'
