Cancer Spread: Do Mechanical Forces Play a Role?
Why are some tumors more likely to spread? The physical properties of the tissue in which cancer starts may be important.
Cancer results from cells that have malfunctioned, dividing uncontrollably, and breaking out beyond their usual constraints. But almost every day I work in a radiation oncology clinic, I ask myself why some cancers are more likely to metastasize to distant body sites. Is it merely the fact that some cells are intrinsically aggressive? Or do other factors play a significant role?
A team at The Rockefeller University (New York City) found that:
“The mechanical properties of tissues that surround pre-cancer cells have a significant impact on the development of two of the most common forms of skin cancer. This causes one type to become far more aggressive and invasive than the other.”
The scientists looked at the most common skin cancer forms, basal cell carcinoma and squamous cell carcinoma. The second is typically more aggressive. Led by postdoctoral fellow Vince Fiore in the laboratory of Dr. Elaine Fuchs (and in collaboration with colleagues at Princeton University), the researchers note that basal cell cancers begin as bud-like clusters of cells. In contrast, squamous cancers start as small folds in the skin tissue.
Fuchs and co-workers induced each of these skin cancer types in two different groups of genetically engineered mice. They then measured their physical properties, as well as those of surrounding tissues. The scientists then made computer models of the epidermis (the outermost layer of the skin) that accurately modeled how the tumors began and their shapes. What causes the two distinct tumor types? It did not appear to be the rapid growth of the cancer cells and the forces they produce as they push on one another.
A set of genes seems to play a central role in determining the physical properties of the basement membrane. This membrane is a floor separating the tumor from the nearby tissues. Now, let’s look at the fascinating findings. Computer models predicted that softening the basement membrane (or increasing its assembly rate) led to the buds that define basal cell cancers. Doing the opposite to the basement membrane led to the folding of squamous cell cancers.
Next, the investigators went a step further. They changed the lab animals’ gene expression, shifting the stiffness and rate of the basement membrane’s assembly. By doing so, they confirmed the accuracy of the computer model. The basement membrane’s mechanical properties influence the shape and behavior of the two main skin cancer types, basal and squamous cell carcinomas, respectively.
The researchers kept going, discovering not only does the basement membrane (floor) physical properties matter a lot but that the roof stiffness matter as well. Squamous cell cancers have a relatively stiff suprabasal roof. This rigidity makes it more likely that the tumors can break through the basement membrane floor and access deeper layers of the skin (and ultimately to distant parts of the body).
Basal cell cancers are associated with a less rigid suprabasal roof, and thus are more likely to remain in place. The architecture of tissues surrounding cancer appears to influence the cancer cell’s behavior. Skin stem cells compose both the underlying basement membrane “floor” and the overlying suprabasal “roof.” As stem cells acquire DNA changes known as mutations, their ability to regulate these structures’ mechanical properties degrades. The rest is predictable.
Someday, we may use analyses of the genes regulating the architecture to understand better which cancers are more likely to spread. Of course, a goal would be to use new drugs to target adverse mutations.
Thank you for joining me today. I’m Dr. Michael Hunter.
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Rockefeller University. “How mechanical forces nudge tumors toward malignancy.” ScienceDaily. ScienceDaily, 2 September 2020. <www.sciencedaily.com/releases/2020/09/200902182436.htm>.