Recent research reports that pancreatic tumors produce a new type of collagen that protects them from attacks by the immune system. This major discovery makes it possible to envisage a new anticancer therapeutic approach, based on the destabilization of this immunoprotective armour.
Type I collagen is the most abundant protein in the human body and plays an essential role in maintaining the structure of bones, tendons, skin and all internal organs.
This structural role comes from the property of collagen molecules to associate with each other to form fibers similar to braided ropes and which have a very high resistance (at equal mass, collagen is surprisingly stronger than steel!)
This supporting role of type I collagen is not limited to normal tissues: several studies carried out in recent years have indeed shown that tumors also produce large amounts of a new type of tumor collagen, which suggests that the presence of these fibers in the microenvironment of cancer cells could participate in tumor progression.
Tumor collagen< /p>
To better understand the function of these collagen fibers of cancerous origin, a team of American researchers looked at the collagen produced by pancreatic adenomas(1). This extremely aggressive type of cancer (only 4% of patients survive more than 5 years after diagnosis) is known to accumulate large amounts of collagen in its microenvironment, suggesting that these fibers may contribute to its invasiveness.
They first discovered that this tumor collagen was different from that produced by connective tissue cells: whereas normally, type I collagen fibers are heterotrimers made up of two chains of collagen α1 and one α2 chain, pancreatic tumor collagen was instead formed of homotrimers containing three identical 1-chains. This may seem like a trivial difference, but subsequent experiments revealed that this modification significantly modulated the properties of cancer cells.
On the one hand, collagen homotrimers strongly activate tumor growth and , on the other hand, these homotrimers give tumors a strong resistance to the action of killer T lymphocytes, normally involved in the elimination of cancer cells.
Immunity in breakdown
To confirm this immunosuppressive effect of collagen of cancerous origin, the researchers manipulated the genetic material of the mouse models in such a way as to specifically eliminate type 1 collagen produced by pancreatic tumours.
The result is quite spectacular, with a marked reduction in the growth of cancerous cells, accompanied by an increase in the quantity of killer T lymphocytes in the tumours. The elimination of type 1 collagen of tumoral origin is therefore sufficient to restore anticancer immune activity, which suggests that this collagen would contribute to the rapid growth and very aggressive nature of pancreatic cancer by participating creating an immunosuppressive environment, which allows cancer cells to grow without interference from the immune system.
Finding a crack in the armor
< p>As mentioned before, collagen fibers are very resistant structures and therefore do not represent valid therapeutic targets. In contrast, the study authors showed that abnormal type 1 collagen (homotrimeric) binds specifically with a receptor present on the surface of cancer cells (integrin α3) and that this interaction is essential for the tumor growth and the creation of an immunosuppressive climate.
Since this collagen is only found in tumors, this discovery therefore suggests that it would be possible to specifically pierce the armor of collagen that protects tumors by targeting integrin α3 and/or the proteins associated with it. New drugs in sight, against one of the most formidable cancers!
- (1) Chen Y et al. Oncogenic collagen I homotrimers from cancer cells bind to integrin and impact tumor microbiome and immunity to promote pancreatic cancer. Cancer Cell, published July 21, 2022.