At some point in our lives, many of us will undergo some form of cancer screening, which can look for the presence of cancerous cells before we may even experience any symptoms. The goal for these screening tests is to detect cancer early, while it is in a ‘precancerous stage’, when it may be easier to treat, therefore hopefully preventing the development of potentially deadly cancers. This type of approach has been very important in reducing cancer-related deaths, particularly for cervical, breast, and colon cancers. However, not all precancers are created equal. In fact, a surprising number of precancerous lesions may never go on to develop into cancer at all. When considering the toll that patients may experience when being told they may have a precancerous lesion warranting preventative treatments such as surgery, having a greater understanding of which precancerous lesions will or will not progress to full disease could be an invaluable way to provide the best quality of care to patients. On top of this, understanding the biology of precancerous tissue, which is likely less molecularly and biologically complex than cancerous tissue, could help inform novel and more effective therapeutic options.
Recently, Drs. Ming Yu, William Grady and Neelendu Dey, from the Translational Science and Therapeutics Division at Fred Hutch, contributed to a large collaborative publication titled “The Hallmarks of Precancer” in Cancer Discovery. A nod to the seminal paper published in 2000 titled “Hallmarks of Cancer,” this work highlights an overview of the current understanding of the biological and molecular underpinnings of precancerous lesions and risk factors for their development into cancer. This work grew from a large multi-site NIH-funded program called Translational and Basic Science Research in Early Lesions (TBEL), which is a “consortia of investigators who are interested in trying to understand the pathogenesis of pre-cancer”, explained Dr. Grady. Thinking about defining and discussing these topics around precancerous lesions is important, as rates of many cancers have been increasing in recent years, predominantly in older populations, but with an alarming increase seen in younger individuals as well, Dr. Dey pointed out, and their questions focus on “what are the earliest things to look out for to prevent these cancers?”
In the paper, the authors define six ‘hallmarks’ of precancer: age-related genetic changes, epigenetic changes, metabolic changes, hijacked regenerative cell state transitions, immune surveillance failure, and the remodeling of the tissue microenvironment. The most pronounced risk factor for the presence and progression of precancerous lesions is age. The older someone is, the more time they will have had throughout their life to acquire these lesions, and age-related biological changes can result in increased risk of mutations within cells, such as telomere shortening and reduced antioxidant activity. But chronological age is not the only measurement researchers can use here – biological age can relay the state of age-related physiological and molecular changes seen within one’s cells. Your biological age could be higher or lower than your chronological one, and higher biological age is associated with a greater risk of developing precancerous lesions. In addition to these definitions of age, another hallmark that the authors define is epigenetic aging. Epigenetics refer to the non-genetically encoded changes to one’s DNA expression, typically through methylation of sites within the genome, which can accumulate over your lifespan and could be associated with development of precancerous lesions that progress to cancer. The authors go on to discuss macroenvironmental factors that can contribute to biological and epigenetic aging, such as adoption of a Western diet, obesity, socioeconomic marginalization, and healthcare access disparities. Some of the metabolic changes associated with poor diet quality, for instance, can increase risk for some cancer types, such a colon cancer. In an example highlighting how these factors can be compounded, they explain that Vitamin C deficiency, which can increase cancer risk, is more common in populations with food insecurities. To this point, Dr. Grady emphasized that “public policy would be an important opportunity for cancer prevention,” indicating that changes at the national level could help address these types of health concerns that arise from broader socioeconomic disparities.
The next hallmark defined by the author is hijacked regenerative pathways that lead to abnormal cell growth. Cancer can be thought of as uncontrolled cell division, and this process starts early, during the precancerous stage. When cell or tissue damage occurs, regenerative processes get to work either through proliferation of tissue stem cells, or through a process called metaplasia, where certain cell types can change into another cell type that is better suited for the changes in their microenvironment that are causing damage. Prolonged engagement of these regenerative processes can result in dysregulated and rapid renewal and differentiation of cells, particularly if they accumulate DNA damage. Dr. Dey is particularly interested in how the microbiome can promote tissue damage and inflammation resulting in dysregulated repair pathways that can result in precancerous development.
If cells manage to initiate tumorigenesis our immune system needs to catch these tumorigenic cells, which is typically quite good at. It is when this surveillance fails that cells can continue to divide and grow into cancerous lesions. Factors such as age, obesity and chronic inflammation can potentiate these poor immune responses. Related to how the immune system can detect cancerous cells is how the tissue microenvironment changes to facilitate the growth of these malignant lesions. Dr Grady has been interested in trying to define how the microenvironment can contribute to these dysfunctional immune responses and tumor progression, defining fibroblast senescent-associated secretory phenotypes, a discovery that was also recently highlighted in Science Spotlight and can be found here.
When it comes to considering the progression from precancer to cancer, there is still so much we do not understand: who is truly at risk, how do we prevent progression, how do we even prevent precancerous development at all? Indeed, there is much that the authors could have expanded on as well, as Dr. Grady noted, “If we’d been given carte blanche, this could have been 10 times the length.” Dr. Dey expressed that “We wanted to make as comprehensive of a document as possible, but also something that would be interesting for people to read; something provocative and stimulatory.” The discussion emphasized in the Hallmarks of Precancer helps highlight the complex nature of external and internal factors that are associated with risk and serves as a platform to define important questions and considerations moving forward. It is the hope that one day interventions can be targeted through approaches such as public policy, which could alleviate health disparities among the broader population, or therapeutic interventions at the precancer stage.
Stangis MM, Chen Z, Min J, Glass SE, Jackson JO, Radyk MD, Hoi XP, Brennen WN, Yu M, Dinh HQ, Coffey RJ, Shrubsole MJ, Chan KS, Grady WM, Yegnasubramanian S, Lyssiotis CA, Maitra A, Halberg RB, Dey N, Lau KS. The Hallmarks of Precancer. Cancer Discov. 2024 Apr 4;14(4):683-689. doi: 10.1158/2159-8290.CD-23-1550. PMID: 38571435.
The Spotlight work was funded by the NIH TBEL grant.
Fred Hutch/University of Washington/Seattle Children's Cancer Consortium members Drs. Neelendu Dey and William Grady contributed to this work.