What is squamous cell carcinoma?  Squamous cell carcinoma is a type of cancer, frequently found on the skin.  In light-skinned people, it generally appears where there’s been lots of sun exposure (why you should protect your skin every day, and not use tanning beds).  In dark-skinned people, it’s seen in areas with chronic scarring or on the lower legs (Lee Lim, 2022 and www.aad.org).  It can also appear in genital areas, and is thought to be caused by human papillomavirus (HPV) infection.  HPV infection can be prevented by a vaccine that kids can start getting at age 11, but is available for patients 9-45 years, depending on risk factors.  The CDC (2021) says that HPV infections are so common that almost everyone will have some type of HPV during their lives.  The vaccine helps prevent over 90% of the cancers that HPV can cause, which makes two or three needlesticks sound like a good trade-off for avoiding cancer.

What is collagen III?  Before starting on “what is collagen III”, what is collagen?  Collagen is a protein found in your skin, muscles, bones, tendons, ligaments, and other connective tissues (Cleveland Clinic, 2022).  It’s found throughout your musculoskeletal system because its job is to support and strengthen your body. 

Collagen III is one type of collagen, composing anywhere from 5 to 20 percent of the collagen in your body.  It’s primarily found in your muscles, arteries, uterus, and bowel (Kuivaniemi, 2019).  We all know how important it is that these organs are strong, so it’s no surprise that mutations in the collagen III gene are linked to severe illnesses, such as vascular Ehlers Danlos syndrome, a connective tissue disorder.  It’s also linked to life-threatening emergencies, such as arterial, uterine, and bowel ruptures.  Arterial ruptures lead to patients bleeding out and dying quickly and bowel ruptures can allow fecal matter to freely float around in your abdomen.  Uterine ruptures can be deadly for mom and baby, as mom might bleed out if not controlled and the baby is exposed to the entire abdomen, instead of just its little nest inside the uterus.

 If collagen III can cause all these other diseases, can it cause cancer too?  Good question!  In 2019, Kuivaniemi and Tromp found that higher levels of collagen III correlated to more severe cancers, specifically gliomas (brain cancers).  However, Mount Sinai found that cancer cells were using collagen III to keep themselves in a dormant, resting phase.  How do you know which is accurate?  How do you know what to do to prevent getting cancer?  Until more research is done on the effects of collagen III in cancer, it’ll be hard to know which researchers are on the right path.  Until then, it’s important to remember that correlation does not equal causation.  Right now, engaging in a healthy lifestyle and following recommendations for cancer screenings are the best way for us to prevent cancer. 

Draw collagen III (Boudko and team, 2008)                         

Research done on this link between collagen III and cancer has revealed lots of information.  First, we’ve learned that there are visible (with the right imaging set up) changes in the collagen III in the extracellular matrix (ECM) around cancer cells, depending on whether they’re in a dormant state or not (Di Martino, 2022, p 91).  Around a dormant cell, the collagen III looks very wavy and goes in several directions, looking a bit like a net.  Around proliferative cells, it’s all straight and arranged in the same direction (Di Martino, 2022, p 92).  To remember it easily, around dormant cells that aren’t growing, the collagen looks like a net, because they’re stuck.  Around the proliferative cells that are growing quickly, the collagen is all pointed in the same direction, like a straight stretch of road where you speed up while driving.  They also conducted imaging on tumor samples and healthy tissue, which shows the same thing as the individual cells did.  The tumor samples had straight collagen III, the healthy tissue had a net of collagen III.

While reviewing the samples, Di Martino (2022, p 92) looked at the percentage of cells in the different growth phases in the different samples.  Individual cells sat in a G1 or G0 phase, simply living, existing, but not multiplying.  Once there was a group of cancer cells, a metastasis, they saw cells in all phases of growth.  As long as the cells remained isolated from each other, they refused to grow.

When they looked at the amount of collagen around these cells, they saw that the ECM matrisome (consider it a recipe for a specific ECM) was 55% collagen peptides in the dormant cells, and only 36% in the proliferative cells (Di Martino, 2022, p 92).  Again, we can use our trick of thinking of the collagen III as a net, holding the dormant cells in dormancy.

Using the fact that collagen III seemed to be holding these cancer cells in a dormant state, they looked into using collagen III to prevent tumor growth.  They injected proliferative cells into mice, but three of the injections contained collagen as well.  The control, collagen I, and collagen IV injection sites grew tumors, as expected.  The collagen III site, however, grew a much smaller tumor than the other three.  They repeated this experiment, injecting a mouse on one side with the control and on the other side with the collagen III containing injection.  On the side with collagen III added, there was noticeably smaller growth (Di Martino, 2022, p 93).  The collagen III continued to minimize the growth of cancer cells.

Was collagen III able to successfully decrease the number of cells going through S/G2?

Now that we’ve determined multiple times that collagen III is controlling cancer growth, what about turning this into a tool we can use?  Di Martino’s team grew tumors in mice.  When they went in to surgically remove the tumors, they treated the wound with a scaffold, either a control scaffold or a collagen III impregnated scaffold.  Mice treated with the collagen III scaffold had a 20% chance of tumor relapse.  Mice treated with the control scaffold had an 80% chance (2022, p 93).  Imaging at recurrence showed that mice treated with the collagen III scaffold had fewer cancer cells, and they were in the G0 phase (just existing, no multiplication).  The control group’s imaging showed masses growing, with cells in all stages of growth (Di Martino, 2022, p 93-94).

This is still relatively new research, published only last year.  However, if scaffolds impregnated with collagen III were used every time someone had surgery to remove cancer, consider the decrease in relapse cases.  What about a regular injection in a tumor site, or a pill that would freeze the cancer in your body until surgery?  What about a daily pill for patients with inoperable cancer, that would freeze the growth of their tumor, giving them more time with their family or more time until a feasible surgery plan was made?

Reference list

Boudko, S., Engel, J., Okuyama, K., Mizuno, K., Bachinger, H.P. and Schumacher, M.A. (2008). Crystal Structure of Human Type III Collagen Gly991–Gly1032 Cystine Knot-containing Peptide Shows Both 7/2 and 10/3 Triple Helical Symmetries. [online] Available at: https://www.jbc.org/article/S0021-9258(20)60441-0/pdf.

Centers for Disease Control and Prevention. (2019). Vaccine Information Statement. [online] Available at: https://www.cdc.gov/vaccines/hcp/vis/vis-statements/hpv.html.

Cleveland Clinic (2022). Collagen: What it is, Types, Function & Benefits. [online] Cleveland Clinic. Available at: https://my.clevelandclinic.org/health/articles/23089-collagen.

Di Martino, J.S., Nobre, A.R., Mondal, C., Taha, I., Farias, E.F., Fertig, E.J., Naba, A., Aguirre-Ghiso, J.A. and Bravo-Cordero, J.J. (2022). A tumor-derived type III collagen-rich ECM niche regulates tumor cell dormancy. Nature Cancer, [online] 3(1), pp.90–107. doi:https://doi.org/10.1038/s43018-021-00291-9.

Kuivaniemi, H. and Tromp, G. (2019). Type III collagen (COL3A1): Gene and protein structure, tissue distribution, and associated diseases. Gene, [online] 707, pp.151–171. doi:https://doi.org/10.1016/j.gene.2019.05.003.

Lee Lim, MD, J. and Asgari, MD, MPH, M. (2022). UpToDate. [online] www.uptodate.com. Available at: https://www.uptodate.com/contents/cutaneous-squamous-cell-carcinoma-cscc-clinical-features-and-diagnosis?search=squamous%20cell%20carcinoma&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1.

reports.mountsinai.org. (n.d.). A Promising Strategy for Preventing Cancer Metastasis and Enhancing Dormancy. [online] Available at: https://reports.mountsinai.org/article/tisch2022-12-_cancer-metastasis-and-dormancy.