It’s Not Your Fault: Cancer as a Multifactorial Disease
Cancer is relentless and sneaky. It’s not your fault that your dog has cancer. It’s not just one thing that causes it, but a cascade of complex events that ultimately lead to cancer development.
- When veterinarians say “cancer is a multifactorial disease,” they mean that it does not have just one cause. Many things must go wrong for cancer to start, take root, and grow into a tumor.
- There are many risk factors for dog cancer, and most of them are out of our control.
- It’s not your fault that your dog has cancer. Even dogs that are fed the “perfect diet” and live in relatively “clean” environments can develop cancer.
It Is Not Your Fault
Cancer has been around forever. One of the biggest reasons we see cancer in our aged dogs is that they can and do get older. We have become much better dog parents, feed healthy well-balanced diets, vaccinate for infectious disease, participate in regular vet visits, minimize wandering, and so on. Because of this our dogs reach the age that they either succumb to organ dysfunction/disease or cancer.1 Similar things have happened to us humans as we also live longer. As a multifactorial disease, cancer doesn’t have “just one cause” and no one is at fault if it happens.
Multifactorial Disease = There Is No One Cause
Cancer is a multifactorial disease. Simply defined, cancer is the growth of abnormal cells that become malignant and often spread (metastasize) to other parts of the body. Everyone makes mistakes, even cells. Cancer begins as a mutation in cellular DNA. Most of the time, the body removes or corrects the mutation. Sometimes, however, the change persists. When there are too many mutations the cells start to grow into a tumor.
There are numerous risk factors involved, including:2
- Environmental chemicals
- Dietary excess/deficiencies
Additionally, cancer does not develop from a single insult to a cell, but from multiple changes that occur before the cell even becomes a cancer. This happens over time, which is why older dogs are more likely to have cancer.3
Cells do not read all parts of DNA. Epigenetic factors can change which parts of the DNA a cell reads and which it ignores.
What are epigenetic factors? There are many, but you could think of them as “environmental” factors. Smoking (or secondhand smoke), obesity, lack of sleep, diet, exercise, environmental pollutants, and psychological stress are all examples of epigenetic factors that might affect the way a cell reads its DNA code.
Epigenetic factors (together called the epigenome) don’t change the DNA itself. But epigenetics can change what is ultimately translated from the DNA into the cell’s activities.
Epigenetic factors at the cellular level include:4
- DNA methylation
- histone modification
- nucleosome remodeling
- non-coding RNA.
Epigenetic abnormalities in cells are potentially reversible but can mistakenly turn on pathways that alter gene function and can result in cancer.5
Cancer cells evade the immune system through a variety of complex interactions including restricting antigen recognition (immune cells cannot recognize cancer cells as abnormal), inhibiting immune system including cytokines (signaling proteins), causing T cell exhaustion, and limiting nutrients to the immune system cells creating a tumor microenvironment.6 Additionally, pro-inflammatory mediators are known to contribute to tumor development. This is one reason obesity is considered a risk factor for cancer. Fat cells secrete many cellular mediators that contribute to a low-level state of inflammation in the body.7
Tumor Microenvironment (TME)
Tumor microenvironment is the environment surrounding the cancerous cells, designed to promote fast cell growth, to spread through the blood or lymphatics, and to suppress the immune system so the tumor can avoid death.8 Additionally, cancer cells need a lot of nutrition for growth. Tumor associated macrophages are abundant in the TME, providing nutrients to the cancer cells while also depleting nutrition for the immune cells.6,9
Ultimately, not every mutation leads to cancer. It is the accumulation of mutations that causes a tumor to form. Additionally, specific mutations are often associated with specific-organ cancers.2
There are also cancer factors that are yet to be discovered. Genetics, epigenetics, and the immune system are all complex multifactorial processes in their own right but they interplay with each other adding another layer of complexity. Hopefully with time and research we will understand more about how cancer forms so that further prevention can happen in the future.
You Did Not Cause Your Dog’s Cancer
Remember, multiple factors contribute to cancer. There is not a single thing that we as owners do that will result in cancer in our dogs. Unfortunately, as we have become caretakers, our dogs are living long enough to develop cancer. The same thing happens to us as humans. Fortunately, doctors are getting better at diagnosing and new treatments are being developed all the time, to help us manage this disease process.
- Tanaka M, Yamaguchi S, Iwasa Y. Enhanced risk of cancer in companion animals as a response to the longevity. Scientific Reports. 2020;10(1). doi:10.1038/s41598-020-75684-4
- Iranzo J, Martincorena I, Koonin EV. Cancer-mutation network and the number and specificity of driver mutations. Proceedings of the National Academy of Sciences. 2018;115(26):E6010-E6019. doi:10.1073/pnas.1803155115
- Fleming JM, Creevy KE, Promislow DEL. Mortality in North American dogs from 1984 to 2004: An investigation into age-, size-, and breed-related causes of death. Journal of Veterinary Internal Medicine. 2011;25(2):187-198. doi:10.1111/j.1939-1676.2011.0695.x
- Dawson MA, Kouzarides T. Cancer epigenetics: From mechanism to therapy. Cell. 2012;150(1):12-27. doi:10.1016/j.cell.2012.06.013
- Sharma S, Kelly TK, Jones PA. Epigenetics in cancer. Carcinogenesis. 2009;31(1):27-36. doi:10.1093/carcin/bgp220
- Kim SK, Cho SW. The evasion mechanisms of cancer immunity and drug intervention in the tumor microenvironment. Frontiers in Pharmacology. 2022;13. doi:10.3389/fphar.2022.868695
- Marchi PH, Vendramini TH, Perini MP, et al. Obesity, inflammation, and cancer in dogs: Review and Perspectives. Frontiers in Veterinary Science. 2022;9. doi:10.3389/fvets.2022.1004122
- Labani-Motlagh A, Ashja-Mahdavi M, Loskog A. The tumor microenvironment: A milieu hindering and obstructing antitumor immune responses. Frontiers in Immunology. 2020;11. doi:10.3389/fimmu.2020.00940
- Dennis KL, Blatner NR, Gounari F, Khazaie K. Current status of interleukin-10 and regulatory T-cells in cancer. Current Opinion in Oncology. 2013;25(6):637-645. doi:10.1097/cco.0000000000000006
- Halios CH, Landeg-Cox C, Lowther SD, Middleton A, Marczylo T, Dimitroulopoulou S. Chemicals in European residences – part I: A review of emissions, concentrations and health effects of Volatile Organic Compounds (vocs). Science of The Total Environment. 2022;839. doi:10.1016/j.scitotenv.2022.156201
- Lane AN, Higashi RM, Fan TW-M. Metabolic reprogramming in tumors: Contributions of the tumor microenvironment. Genes & Diseases. 2019;7(2):185-198. doi:10.1016/j.gendis.2019.10.007
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