Cancer is a devastating disease on its own, especially if diagnosed in the later stages of its development. Some cancer survivors unfortunately go through more than one scare: when they've found out that the cancer has returned. This relapse can be particularly challenging both physically and emotionally. Understanding why cancer can come back, including the roles of cellular quiescence and dormancy, is crucial for developing more effective treatments.
Understanding Cancer Relapse
Cancer relapse, or cancer recurrence, occurs when cancer cells start growing in the body again after seemingly successful initial removal or treatment. The cells can recur in the same area that they initially started to grow in, called local recurrence, or they can reappear in a new spot, further away from where they started. This is called distant recurrence. Cancer can also recur in the lymph nodes and/or tissues near the original site, called regional recurrence.
When cancer relapses, it is usually more aggressive than how it was initially, especially if it spread to other parts of the body or has become resistant to common forms of treatment. Hard-to-treat and aggressive cancers will likely have higher recurrence rates and may recur sooner, within weeks to months after initial treatment. For example, glioblastoma has almost a 100% recurrence rate due to its aggressiveness. There is no fool-proof way of knowing whether a cancer will return and is dependent on a variety of factors. Type of cancer, stage of cancer when it was diagnosed, and how fast the tumor grows, are a few factors that doctors will consider. However, it is often not beneficial to know exactly if and when one's specific cancer may return.
The Role of Quiescence
On a cellular level, a likely reason for recurrence is that some of the original cancer cells were in a state of cellular quiescence (pronounced kwy-ess-uhns). Cellular quiescence is a reversible state in which the cells temporarily stop growing or replicating (Figure 1). They do not die, instead, this state is referred to as a period of rest. These cells have very low energy and metabolism levels. It is important to note that quiescence is not specific to cancer cells. In fact, it is a normal occurrence in healthy cells. Cells may enter a state of quiescence due to a variety of internal or external factors. For example, sources of nutrients may temporarily decrease or there may be low oxygen levels within the cell environment causing it to enter into quiescence. When in this state, cancer cells are inactive and remain protected from all types of treatment, including chemotherapy and radiotherapy.
Figure 1. Cellular Quiescence and the Cell Cycle. Adapted from: Cellular quiescence in budding yeast.
Cancer Dormancy
Like quiescence, dormancy is a state of inactivity. While quiescence is associated with short-term inactivity, dormancy is more long-term. Cancer dormancy can arise from cells that are in a quiescent state. Cancer cells can go into dormancy at different times, such as during the initial tumor formation, when they spread to other parts of the body, or during metastasis (when cancer cells form new tumors in other areas). There are two types of dormancy: primary tumor dormancy and metastatic dormancy. Primary tumor dormancy happens when the tumor becomes inactive, or stops growing, at the original tumor site. Metastatic dormancy happens when cancer cells stay inactive at a new site after spreading. This dormancy can be caused naturally or by treatments like chemotherapy or radiotherapy. In both cases, the dormant cancer cells can survive and avoid further treatment, leading to relapse months or even decades after the original tumor is removed.
Individual or small groups of cancer cells may enter a state of quiescence or dormancy before or during the time that a patient is diagnosed with cancer. However, because these groups of cells are so tiny, doctors are unable to detect them. Therefore, these cells are often missed, in addition to being resistant to cancer treatment. Much research currently goes into this area of medicine as it is still not clear exactly what allows these cells to be protected from cancer treatment while in this state.
The type of dormancy and length of dormancy periods can vary amongst the different cancer types and can affect each tumor differently. For example, in breast cancer, whether a tumor has estrogen receptors (ER) can affect the relapse timing. Patients with ER-positive breast cancer might experience a relapse between five and 20 years after treatment. In contrast, if recurrence were to happen in patients with ER-negative breast cancer, it is more likely to happen within the first five years after treatment.
Conclusions
Cancer relapse presents a significant challenge for patients. Further research into the mechanisms behind the above-mentioned processes is necessary to develop more effective therapies since current therapies target actively dividing cells. With additional research and a more in-depth understanding, doctors and researchers can improve treatment strategies and ultimately enhance long-term outcomes for cancer patients.
References
For more information, check out these articles:
American Cancer Society. "When Cancer Comes Back". https://www.cancer.org/content/dam/cancer-org/cancer-control/en/booklets-flyers/when-cancer-comes-back.pdf
City of Hope. "What is Cancer Recurrence?". https://www.cancercenter.com/cancer-recurrence
Océane Marescaland and Iain M. Cheeseman. "Cellular Mechanisms and Regulation of Quiescence." https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665062/
Roger R Gomis and Sylwia Gawrzak. "Tumor cell dormancy". https://pubmed.ncbi.nlm.nih.gov/28017284/
Hiroko Endo and Masahiro Inoue. "Dormancy in Cancer". https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6361606/ Assessed and Endorsed by the MedReport Medical Review Board