Role of the extracellular environment in cancer formation
To form a cancer, cells need to accumulate oncogenic mutations that confer tumor-initiating properties. However, recent evidence has shown that oncogenic mutations occur at a surprisingly high frequency in normal tissues, suggesting that mutations alone are not sufficient to drive cancer formation and that other mechanisms, including induction of cell death or terminal differentiation, should promote or restrain oncogene-expressing cells from progressing into invasive tumors.
In a study published in Nature, researchers led by Cédric Blanpain (WEL Research Institute – ULB) discovered new mechanisms that restrain oncogene-expressing cells to give rise to invasive tumors.
For this, the researchers studied in animal models the ability of oncogene-expressing cells in different skin locations (ear and back) to develop basal cell carcinoma (BCC), the most frequent cancer in humans at a single cell resolution. Surprisingly, they found that cells expressing the oncogene in the ear, but not in the skin of the back, gave rise to the typical appearance of invasive BCC. The team found that the extracellular matrix of the dermis is characterised by increased rigidity and a denser collagen network in the skin of the back - resistant to tumorigenesis processes - than in the ear where cells can give rise to invasive cancers. By enzymatically reducing collagen density, the team demonstrated that collagen abundance was a key factor in limiting the invasion and formation of tumours in the skin of the back.
Aging and UV exposure are also associated with decrease in collagen density in the skin. Interestingly, oncogene expression in old mice or following UV exposure, led to skin tumor formation in the skin of the back, demonstrating that the level of collagen expression dictated the competence for skin tumor initiation.
This study demonstrated that the composition of the extracellular environment regulates the regional competence to undergo tumor initiation and invasion and provides a better understanding of cancer formation in humans, with BCC originating preferentially in certain areas of the body such as the ears and nose, which have a different abundance of collagen.
Reference : Bansaccal et al (2023) The extracellular matrix dictates regional competence for tumour initiation, Nature https://doi.org/10.1038/s41586-023-06740-y
Source : Press release ULB