Squamous cell carcinoma (SCC) is the second most common form of skin cancer in the United States. Over one million SCC diagnoses are made in the United States each year. The name comes from the fact that the cancer develops in the squamous cells. These cells make up the middle and outer layer of skin (Mayo Clinic, 2023). Squamous cells are thin and flat and can be found in places like the lungs, mucous membranes, digestive tract, urinary tract. Its major risk factor is too much UV radiation that can come from the sun, tanning beds, or even other sources like the light that cures nail polish (Howell, 2023). People who are less at risk of UV related skin damage such as people black and brown skin can still have SCC. In that case it is more likely to show on skin that is not often exposed to the sun, like the genitals (Mayo Clinic, 2023). The cancer can grow on anyone and if someone with light skin develops SCC in an area that is not often exposed to the sun it is likely that the person has another issue like a weak immune system (Mayo Clinic, 2023). Some people may also be of higher risk due to genetics. Cancer forms in squamous cells due to changes in the DNA of the cell, which causes them to multiply uncontrollably (Yetman, 2022). The most common mutation is found in the p53 gene. Squamous cell carcinoma is often not life threatening and can be treated by surgical removal but if left untreated it can spread and grow larger. Mohs micrographic surgery is the most common treatment method and preferred when SCC is on the face and neck (Howell, 2023). During Mohs surgery a small layer of skin is removed and checked under a microscope to see if cancer remains and more layers are removed until the area is cancer free (MOHs surgery, 2022).
Collagen is the most abundant protein in the body and it makes up bones, skin, hair, muscles, tendons, and ligaments. It has a fiber-like structure that makes connective tissue strong and able to stretch. Collagen gives skin its elasticity and helps nails and hair to stay healthy, but collagen decreases in the body over time and the fibers become loose. Collagen can also decrease due to sun exposure, smoking, excess alcohol intake, lack of sleep, and a sedentary lifestyle (Collagen Types). Ninety percent of collagen in the body is Type I and III Collagen but there are many other types. Collagen III is initially produced by cells as procollagen. Procollagen is a protein consisting of three pro-alpha1(III) chains that form a triple-stranded rope-like molecule.
This rope-like structure gives collagen its ability to stretch and join to make fibrous structures on an amino acid chain (Human Collagen). The main proteins in Type I and III are glycine, proline, alanine, and hydroxyproline but there are 19 total proteins, also known as amino acids. The amino acids are made by fibroblasts which make connective tissue, and osteoblasts that make bone. The amino acids are important for many functions in the body such as maintaining skin, muscles, and bone health (Nutrition, 2016). Type III is especially important for tensile strength and integrity for many organs. The fibers in Type III are smaller than in Type I. It is also what gives blood vessels, arteries, the uterus, and the bowels their structure due to its ability to stretch and allow for more movement. It can ever be found in bone marrow and regulate the production of Type I collagen (Collagen Types). Collagen does not contribute to cancer but tumors use collagen fibrose to build tumors (Miskolczi et al., 2018). There are conflicting studies whether having more collagen can lead to cancer. Most studies show that they are unrelated or that collagen can even help prevent cancer but a doctor should be consulted before taking supplements. Collagen supplements may increase cancer production if there is already a mutation in the cells.
Most deaths by cancer are due to metastases. Metastases is when cancer starts to spread to other areas of the body and becomes proliferative. Many times, cancer can stay dormant in organs and is then diagnosed after the cancer has spread, which makes it harder to treat. The extracellular matrix (ECM) is a meshwork of proteins that works differently for both dormant and proliferative cancer cells and is consistent for single cells and metastases (Di Martino et al., 2021). Proliferative cells (T-HEp3) are active cells that have more linear organization but dormant cells (D-HEp3) lack the same degree of linear organization of collagen fibers. This is the change in the ECM, the structure of the cells is very important to the metastase rate. Collagen III can act as a binding structure due to its fibrils help keep cells dormant and work to slow or stop metastases. Dormant cancer cells use collagen III to enrich the ECM niche since it is also the most abundant collagen protein produced by dormant cancer cells (Di Martino et al., 2021). Nude mice treated with the type III collagen scaffold had fewer cancer cells. These remaining few cells undergo growth arrest in the G0 phase (Di Martino et al., 2021). Cellular dormancy takes place in (G0/G1) and is a reversible growth arrest that can be regulated by how disseminated tumor cells interact with the environment (Di Martino et al., 2021). The G0/G1 cells present nuclear fluorescence which was equally distributed through the S phase and not shown through G2 which precedes mitosis. This showed that dormant cells are in G0/G1 with an ECM that has a weak linear orientation. The solitary cells in G0/G1 that were in the lungs of the mice showed micrometastases and a mixed population of cancer cells at different phases of the cell cycle which demonstrates proliferation. This was because of a change in ECM alignment to a more linear state. Collagen III also decreased the number of cells going through S/G2 phases and used DDR1-mediated STAT1 signaling to slow tumor cell proliferation and sustain dormancy. Nude mice treated with the collagen III scaffold had fewer cancer cells and the cells had nuclear localization in G0. The nude mice did develop tumors with cells at different stages of the cell cycle which shows that the tumors grow at different locations and present themselves differently (Di Martino et al., 2021).
Dormant tumor matrisomes were shown to be made of 55% collagen peptides but proliferative tumors only contained 36% collagen (Di Martino et al., 2021). Collagen III greatly decreases the size of tumors in nude mice and also greatly decreases the rate at which tumors come back. Only 20% of the mice treated with type III collagen scaffolds had cancer come back after tumor surgery, comparatively 80% of the mice in the control group had a relapse (Di Martino et al., 2021). Type III collagen prevents the reawakening and spreading of cancer cells by maintaining cancer cell dormancy in the primary site by targeting the metastatic ECM and changing its structure.
Scientists might be able to look at the collagen fiber alignment to predict tumor recurrence after more research. The research shows that cancer can be detected when collagen fiber alignment around growing cells shows the cell is coming out of dormancy. Doctors may be able to detect this in human head and neck squamous cell carcinomas and mammary cancer models (Di Martino et al., 2021). The type III collagen treatment also showed no effect on cytotoxicity, apoptosis, or viability in cells (Di Martino et al., 2021). Three weeks after the tumor removal in nude mice the collagen fibers showed a low degree of linear orientation around individual tumor cells which is seen in dormant cells.
Dormant cells adhere to collagen more efficiently compared to type III collagen than type I or type IV collagens, proliferative cells adhere best to fibronectin. Cancer cells stop proliferating when there is an abundance of collagen III and show a decrease in phospho-histone H3 protein levels. Stages of cancer can be determined by the degree of linear arrangement of ECM. Early stage I to III and advanced IV can be easily distinguished for advanced HNSCC tumors compared to early-stage indolent tumors (Di Martino et al., 2021).
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Reference List
Collagen Types 1, 2 and 3: What’s The Difference? | Care/of (no date). https://www.takecareof.com/articles/collagen-types-1-2-and-3.
Di Martino, J.S. et al. (2021) A tumor-derived type III collagen-rich ECM niche regulates tumor
cell dormancy, Nature News. Available at: https://www.nature.com/articles/s43018-021-00291-9 (Accessed: 03 December 2023).
Howell, J.Y. (2023) Squamous cell skin cancer. https://www.ncbi.nlm.nih.gov/books/NBK441939/.
Human Collagen Type III (no date). https://www.sigmaaldrich.com/US/en/product/mm/cc054.
Miskolczi, Z. et al. (2018) ‘Collagen abundance controls melanoma phenotypes through lineage-specific microenvironment sensing,’ Oncogene, 37(23), pp. 3166–3182. https://doi.org/10.1038/s41388-018-0209-0.
MOHs surgery (2022). https://www.hopkinsmedicine.org/health/conditions-and-diseases/mohs-surgery#:~:text=What%20is%20Mohs%20surgery%3F,only%20cancer%2Dfree%20tissue%20remains.
Nutrition, E. (2016) Collagen types 1, 2, & 3 – Knowing the important differences. https://blog.energeticnutrition.com/2016/04/collagen-types-1-2-3-knowing-important-differences/.
Squamous cell carcinoma of the skin – Symptoms and causes – Mayo Clinic (2023). https://www.mayoclinic.org/diseases-conditions/squamous-cell-carcinoma/symptoms-causes/syc-20352480#:~:text=The%20squamous%20cells%20make%20up,other%20parts%20of%20the%20body.Yetman, D. (2022) Squamous cell cancer: pictures, symptoms, treatment, and more. https://www.healthline.com/health/squamous-cell-skin-cancer.