2024-02-15 16:44:21
Approximately 70% of ovarian cancers are called “high-grade serous”[2] and have a severe prognosis. Optimizing treatments and developing new strategies therefore constitute major scientific and medical challenges. Today, scientists are interested in a specific cell population: fibroblasts, heterogeneous cells present throughout the body in connective tissues (which ensure the cohesion of other tissues in the body). Cancer-associated fibroblasts (CAFs) participate in the maintenance of the tumor microenvironment, considered an important driver in the development of the disease (e.g. by promoting the spread of metastases). Understanding the role and evolution of CAFs during disease and its treatment is therefore essential to find more effective therapeutic approaches once morest cancer.
The effect of chemotherapy on cancer-associated fibroblasts
Within the Cancer, heterogeneity, instability and plasticity unit (Inserm, Institut Curie), the team led by Dr Fatima Mechta-Grigoriou[3], evaluated the effect of chemotherapy treatment on four CAF populations previously identified in high-grade serous ovarian cancers. Researchers have succeeded in distinguishing several categories of CAF: some, beneficialwould block tumor development, while others, harmful, would participate in the growth of cancer. Scientists have observed thata significant proportion of CAF harmful is inactivated following chemotherapy treatment. However, a variable proportion of these CAFs harmful remains activated despite chemotherapy, with an impact on the effectiveness of the treatment.
CAFs and the immune system
The team wanted to go further and was interested in the interaction between these CAFs harmful and the immune system. Its results reveal that the population of CAF harmful blocks the anti-tumor activity of essential immune cells: CD8+ T lymphocytes. Thus, targeting these CAFs harmful residual, in combination with chemotherapy, might improve the prognosis of patients with ovarian cancer.
« These results suggest that a therapeutic approach specifically targeting these residual harmful CAFs, in addition to chemotherapy, might increase the antitumor activity of CD8+ T lymphocytes and improve cancer treatment and patient prognosis. » explain Dr Fatima Mechta-Grigoriou. « At the Institut Curie, we are currently carrying out the Hospital-University Research project CASSIOPEIA which focuses on these same CAF populations to fight once morest metastases and resistance to treatment in triple negative breast cancers. »
Marking of populations of harmful CAFs (ANTXR1, in red) and intracellular YAP1 proteins (in green) in cells before and following treatments. After chemotherapy, we observe the residual presence of YAP1 in green which might be targeted to increase the effectiveness of chemotherapy. Scale bars, 50 mm
Fibroblasts beyond cancer
Recently published results[4] by the same team also highlighted a role of fibroblasts in the development of chronic kidney diseases, major cause of death worldwide. By accumulating, these fibroblasts cause kidney dysfunction. The scientists thus showed that the presence at diagnosis of particular fibroblasts was predictive of an unfavorable prognosis in the patient.
« The diverse populations of fibroblasts are involved at different stages of pathological development in cancer, but also appear in new and intriguing ways in other pathologies, which considerably broadens our field of research. », concludes the Dr Fatima Mechta-Grigoriou.
[1]The tumor microenvironment is defined as all the cells or biological constituents (blood vessels, immune cells, fibroblasts, signaling molecules, extracellular matrix) which are located around cancer cells and which interact strongly with them.
[2] High-grade serous ovarian cancer is a subtype that develops from epithelial cells.
[3] The Stress and Cancer team at Institut Curie is led by Dr Fatima Mechta-Grigoriou, exceptional research director at Inserm.
[4] Cohen et al., 2024, WNT-dependent interaction between inflammatory fibroblasts and FOLR2+ macrophages promotes fibrosis in chronic kidney disease, Nature Communications, 2024 Jan 25;15(1):743. doi:10.1038/s41467-024-44886-z.
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