Ovarian cancer is one of the most lethal gynecological cancers, often diagnosed at an advanced stage when the cancer has already spread to other organs. Scientists have long suspected that ageing tissues may facilitate the metastasis of ovarian cancer, but the underlying mechanisms were not well understood. Now, a new study by researchers at the Indian Institute of Science (IISc) has revealed how proteins secreted by senescent or aged cells create a favourable environment for ovarian cancer cells to adhere and grow.
Senescence and extracellular matrix
Senescence is a state in which cells stop dividing but do not die, and is associated with ageing and chronic inflammation. Senescent cells secrete various molecules, including proteins that form the extracellular matrix (ECM) – the scaffold that supports and surrounds the cells. The ECM plays an important role in regulating cell behaviour, such as migration, adhesion and proliferation.
The researchers, led by Associate Professor Ramray Bhat from the Department of Developmental Biology and Genetics, used a chemotherapy-induced senescent model to mimic the effects of ageing at the cellular level. They exposed tissues from the lining of body cavities in mice and human tissue-like cell sheets to chemotherapeutics, inducing senescence. They then exposed both young and aged tissues to ovarian cancer cells and observed their interactions under a microscope.
Cancer cells prefer aged tissues
The researchers found that ovarian cancer cells preferentially settled on aged tissues and positioned themselves closer to the senescent cells. They also noticed that the cancer cells stuck strongly to the ECM around the aged cells, and eventually cleared the aged cells away. Using computer modelling and experiments, they identified that it was the ECM, not the senescent cells themselves, that attracted and retained the cancer cells.
The team also found that the ECM formed by the senescent cells had higher levels of proteins such as fibronectin, laminin and hyaluronan compared to the ECM formed by the young cells. These proteins allowed the cancer cells to bind more strongly to the aged cell-ECM, facilitating their adhesion and growth.
Implications for diagnosis and treatment
The study, published in Cellular and Molecular Life Sciences, provides new insights into why ovarian cancer is particularly dangerous and often goes undetected until it is too late. The researchers suggest that identifying matrix proteins could help predict cancer cell deposition in tissues and improve early diagnosis. They also caution that chemotherapy, which is commonly used to treat ovarian cancer, may induce senescence in normal tissues and worsen the outcome by enhancing metastasis.
The researchers propose that targeting senescence-associated ECM proteins could be a potential strategy to prevent or reduce ovarian cancer spread. They also highlight the need for further studies to understand how senescence affects other types of cancers and how it can be modulated to improve cancer therapy.