Colorectal cancer: aspirin reduces the rate of tumor cell division and increases the rate of cell death

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Cancer starts when cells start dividing uncontrollably. Scientists have known that taking aspirin can help protect against the development of colorectal cancer – cancer afflicting the colon or rectum – but the exact reason aspirin has this effect has been mostly a mystery.

In a new study published in the journal eLife, researchers at the University of California, Irvine reveal for the first time that aspirin changes the way colorectal cancer cell populations evolve over time, making them less able to survive and proliferate.

“We asked what aspirin does to the Darwinian evolution of cells,” said co-author Dominik Wodarz, professor of population health and disease prevention at the UCI Program in Public Health.

“Cancer arises because cells evolve from a healthy state toward a pathogenic state where the cells divide without stopping. This happens when cells acquire a number of mutations, and these mutations are selected for. We found that aspirin affects these evolutionary processes and slows them down.”

The team found that aspirin alters the birth and death rates of colorectal cancer cells. Specifically, aspirin reduces the rate of tumor cell division and increases the rate of cell death.

The researchers, including the paper’s lead author Natalia Komarova, professor of mathematics, started the work suspecting that aspirin may have a role to play in colorectal cancer’s evolution, wherein the forces of natural selection – or the processes that determine which individuals in a population will survive and reproduce and which will not – govern whether or not cancer cells proliferate to the point where they become harmful or lethal.

“We thought that a slowed development of cancer due to aspirin must somehow arise from a slowed evolution of the cells toward malignancy,” said Komarova.

“What surprised us was that this mechanism could explain the level of protection seen in the human population quite well. In other words, the predicted magnitude was consistent with the protective effect seen in the human population, in epidemiological studies.”

A 2011 clinical trial revealed that people who took 600 milligrams of aspirin each day for two years had a 63% reduction in colorectal cancer occurrence in patients suffering from Lynch syndrome – an inherited condition that increases one’s risk of developing certain types of cancer such as colorectal cancer. Many other studies corroborate those findings, but none until now has investigated a possible evolutionary explanation for why this happens.

“The novel part is really saying that aspirin changes the evolutionary outcome of carcinogenesis,” Wodarz said. “This work is an example showing that mathematical approaches can be very useful to understand complex phenomena in cancer biology; such insights would not be possible to obtain by experimentation alone. It requires the collaboration of empirical biological work and mathematics.”

Now, Komarova and the rest of the team want to find out whether aspirin has similar effects on cancers afflicting other organs in the body.

“If not,” she asked, “in which organs is aspirin protective, and how could we explain these differences in the ability to protect against cancer?”


Cancer Prevention Overview
Cancer prevention for the general population is commonly associated with screening programs with early detection to lower cancer mortality as the primary endpoint. In parallel to this approach, preventive interventions strategies have been investigated to reduce cancer incidence. Therapeutic cancer prevention has great potential, but more research and educational and communication programs for health care providers and the general population are needed.

Colorectal cancer (CRC) is still among the more common cancers in terms of incidence and mortality worldwide [1]. A recent publication focusing on European countries showed significant differences in CRC mortality and incidence, between countries where screening programs were well established, compared to countries that developed them only recently or those with no screening programs [2]. Countries with more extensive screening showed a significant CRC mortality reduction. The impact of high screening coverage shows an initial increase of cancer cases found within the first and second rounds of screening and a subsequent decline. In contrast, CRC incidence was stable or increased in countries lacking screening programs.

Screening programs are designed for the general population, and, especially in countries where there is publicly funded health care, age is the only discriminant to access to the program. In the era of precision medicine, screening programs should be personalized. For instance, in a recent paper by Helsingen et al. [3], a CRC screening program based on a predictive risk model was proposed. The expert panel suggested that subjects with a cancer risk ≥3% at 15 years should undergo screening with one of the available screening options, whereas those with cancer risk <3% at 15 years might not need to be screened. Helsingen’s proposal avoids CRC screening for very low-risk populations; however, we should consider more accurate screening tests for high-risk individuals to improve effectiveness even if this is more invasive.

This strategy requires an active interaction between healthcare providers and the population to identify individual risk and to reach a proper balance between health assistance and personal preferences, the potential benefits and disadvantages of the test/program offered, and to obtain a real shared and informed decision. Proper cancer risk awareness significantly improves preventive program adherence [4].

Proposing a preventive treatment with a drug, which implies possible side effects and a long treatment period, underlines the importance of stratifying people based on their own risk. Higher disease risk may justify a different risk/benefit ratio of a specific drug intervention.

Large cohort studies on cancer prevention, particularly on CRC prevention, are hampered by the time length, as they could take at least ten years before they produce evidence of the effect on cancer events. At the same time, the success of cardiovascular prevention at long-term follow-up was based on studies with reliable surrogate biomarkers. This supports the effectiveness of preventive interventions in the short–medium term. Hence the need to find and validate effective biomarkers to identify high-risk individuals better and predict the intervention efficacy in cardiovascular disease and CRC.

The primary clinical marker for CRC prevention is adenoma due to its role as a precancerous lesion, and polypectomy reduces the risk of CRC [5]. Adenoma detection and recurrence can also be evaluated to verify the efficacy of preventive drug interventions based on many lines of clinical evidence of aspirin use in CRC prevention [6].

However, a very recent meta-analysis of randomized clinical trials [7], comparing the efficacy of daily aspirin use to placebo in healthy individuals at the time of study entry, showed controversial results. A significant 22% incidence reduction for advanced lesions (i.e., adenomas with a villous component, adenomas ≥1 cm in diameter, adenomas with high-grade dysplasia, and/or invasive cancer) was seen at 5 years but not at 3 or 10 years.

The subgroup analysis showed that the effect was restricted to the aspirin medium-high doses (≥300 mg/day). An opposite trend was seen for adenomas, where a significant 16% reduction was seen at 3 years with the low-dose aspirin group (≤160 mg/day). No difference was observed in adverse events.

The major limitation to interpreting these data is missing information about the duration of aspirin intake. Interestingly, the positive effect for adenomas is seen early with a lower dose. For advanced lesions, it is seen at longer follow-up with higher doses. These findings suggest that low- and high-dose aspirin can affect different mechanisms of disease biology, as discussed below.

The systematic review and meta-analysis of randomized clinical trials by Veettil et al. [8] showed positive results on a population with a previous history of CRC or adenomas. Low-dose aspirin for 2–4 years significantly reduced the recurrence of any adenoma, but the data for advanced adenomas were less robust. Additionally, selective cyclooxygenase (COX)–2 inhibitors (coxibs) significantly reduced adenoma recurrence. Additionally, a trend of increased risk after quitting the drug, particularly for coxibs, was shown [8].

A recent large cancer screening trial over a median duration of 13 years [9] showed that the traditional nonsteroidal anti-inflammatory drug (NSAID) ibuprofen (≥30 versus <4 pills per month) decreased the risk of advanced distal adenoma in standard risk individuals. Aspirin was more effective on adenoma recurrence (≥30 versus <4 pills per month). Both NSAIDs showed a preventive effect on cancer incidence except for rectal cancer [9]. This study has several limitations, including missing data on (1) the NSAID use with proximal adenomas; (2) the NSAID dose taken; (3) the NSAID use information subsequent to baseline. Altogether, these points make the results hard to interpret.

Aspirin and Cancer Prevention
Many lines of clinical evidence support the potential role of aspirin in cancer prevention [6]; however, its use in clinical practice is held back by the possible risk of side effects, mainly bleeding [10]. Considering data from the last decade, the meta-analysis by Rothwell et al. has to be mentioned [11].

It included eight randomized clinical trials for primary or secondary prevention of vascular disease. Participants were randomized to aspirin versus placebo, the aspirin dose covering a wide range (from 75 to 1200 mg per day). Data showed a death reduction from different cancers starting after the fifth year of follow-up. Within the second decade, specifically for CRC, a statistical significant death reduction reached 49%, maintaining a 40% reduction with longer follow-up. For CRC, aspirin, even at the lower dose of 75 mg/day used for cardiovascular disease prevention, reduced cancer mortality and cancer incidence [12].

The incidence decreased by 24% (p = 0.02) for colon cancer, reaching a 55% reduction (p = 0.001) for proximal colon, but a not significant 10% reduction for rectal cancer was shown. The risk-reducing effect of aspirin on cancer is seen overall in the gastrointestinal tract. Further analyses of cancer events in randomized clinical trials with aspirin [11,13,14,15] for cardiovascular disease prevention showed: (1) detectable benefits at daily doses as low as 75 mg; (2) an apparent chemopreventive effect of aspirin saturable at low doses (i.e., 10- to 20-fold higher doses were not more effective than lower doses); and (3) a chemoprevention apparent effect in men at high cardiovascular risk treated with a 75-mg of controlled-release aspirin.

A recent meta-analysis of observational studies [16] showed a relative risk (RR) of 0.73 (95% CI, 0.69–0.78) for CRC; RR 0.67 (95% CI, 0.57–0.79), and RR 0.61 (95% CI, 0.0.49–0.77) respectively for squamous esophageal cancer and adenocarcinoma of esophageal and gastric cardia; RR 0.64 (95% CI, 0.51–0.82) for stomach cancer; RR 0.78 (95% CI, 0.68–0.89) and RR 0.62 (95% CI, 0.44–0.79) for pancreatic cancer and hepato-biliary tract respectively.

The risk reduction observed was similar between colon and rectal cancer. The authors showed a dose- and time-dependent linear response for CRC. In contrast to the results of the metanalyses of randomized clinical trials, a dose-response was apparently detected in this study. Out of 11 studies, a significant 10% reduction with 75 mg/day up to 50% with 500 mg per day was shown. Out of 22 studies, a time-dependent risk reduction was found, i.e., 4%, 19%, and 29% reduction were seen at one, five, and ten years of treatment, respectively [16].

Recent observational studies strengthened the positive effect of regular aspirin use to reduce CRC risk and specific mortality [17,18]. The data were stratified by pre- and post-cancer diagnosis aspirin intake to investigate the effect on cancer mortality.

Overall, pre and post intake showed a significant 30 to 40% mortality reduction. The finding was that long-term aspirin use before a diagnosis of nonmetastatic CRC may be associated with lower CRC-specific mortality after diagnosis, consistent with possible inhibition of micrometastases before diagnosis. Recently, Lau et al. [19] showed that standard cardiovascular disease risk factors are associated with increased risk of future cancer in participants (free of cancer at baseline) of FHS (Framingham Heart Study) and PREVEND (Prevention of Renal and Vascular End-Stage Disease).

These are prospective, longitudinal community-based observational cohort studies [20,21,22]. These data suggest that the association between cardiovascular health and future cancer is attributable to shared risk factors [19]. The study by Zhang et al. [18] included a large population and a long follow-up, thus showing evidence that a clearer benefit is detected only after 10 years of aspirin use, and it persists despite continuing use or not. This 10-year latency before the benefit of aspirin-based chemoprevention was previously shown in several studies.

Mechanisms driving aspirin potential in CRC chemoprevention are still under debate and will be discussed below.

Overall, there is no doubt that aspirin can play a significant role in cancer prevention, especially for large bowel cancer; moreover, low-dose aspirin is recommended for the management of acute ischemic syndromes (both coronary and cerebrovascular) and for the prevention of their recurrence [10]. However, the role in the primary prevention of atherothrombosis and cancer remains controversial because of the uncertain balance of the potential benefits and risks. The main hazard of low-dose aspirin therapy is hemorrhage due to inhibition of platelet function, which is an important component of primary hemostasis. In middle-aged patients, the increased risk of bleeding corresponds to an estimated absolute excess of approximately 1–2 major bleeding complications per 1000 patients treated with low-dose aspirin for 1 year; the excess risk is smaller in young people and substantially higher in elderly individuals and in those with a history of ulcer bleeding [10].

Clinical decision-making in this setting is guided by evaluating the risk of cardiovascular disease, CRC, and bleeding [23]. The U.S. preventive services task force (USPSTF) recommends initiating low-dose (81mg/day) aspirin use for CRC primary prevention in adults aged 50–59 years or 60–69 years who have a 10% or greater 10-year cardiovascular disease risk, are not at increased risk of bleeding, have a life expectancy of at least 10 years, and are willing to take low-dose aspirin daily for at least 10 years. In contrast, evidence is insufficient among those aged 50 years old and younger or 70 years and older.

Based on new analyses of the evidence from primary cardiovascular disease prevention [24] and the results of the ASPREE trial [25], the USPSTF has changed the age ranges and grades of its recommendation on aspirin use (https://www.uspreventiveservicestaskforce.org/uspstf/draft-recommendation/aspirin-use-to-prevent-cardiovascular-disease-preventive-medication#bootstrap-panel–4, accessed on 1 December 2021).

The decision to initiate low-dose aspirin use for the primary prevention of cardiovascular disease in adults ages 40 to 59 years who have a 10% or greater 10-year cardiovascular disease risk should be an individual one. USPSTF recommends against initiating low-dose aspirin use for the primary prevention of cardiovascular events in adults age 60 years or older. However, persons who are not at increased risk of bleeding and are willing to take low-dose aspirin daily are more likely to benefit.

The ASPREE trial put a substantial warning against using aspirin in elderly subjects [25]. The trial enrolled 19,114 persons with a median age of 74 years. Follow-up was stopped at 4.7 years since aspirin use did not improve the primary endpoint, i.e., disability-free survival (death, dementia, or persistent physical disability), and a higher rate of hemorrhagic events was obverted (HR, 1.38; 95% CI, 1.18–1.62). In particular, the overall mortality was higher in the aspirin arm (HR, 1.14; 95% CI, 1.01–1.29) with a major contribution of cancer-related mortality (HR, 1.31; 95% CI, 1.10–1.56). The message was that in the elderly, the risk-benefit ratio of primary prevention with aspirin is not advisable. Notably, cancer prevention is not realistic in an older population since a long time is needed to obtain anticancer protection.

Nevertheless, dose and duration remain open issues.

Precision medicine by tailoring drug treatment to specific individuals or populations could help to improve efficacy while reducing side effects; however, selecting the appropriate target population requires information on genetic and other biomarkers, together with environment and lifestyle for each person.

These detailed patient data will be integrated using structured ontological approaches, analytics, mathematics, and statistics which constitute the tools of quantitative systems pharmacology; this strategy can predict drug efficacy and safety on an individual basis. The selection of patients and the dose for aspirin treatment will be performed using machine learning algorithms based on demographic, clinical, genetic, and biochemical information, such as BMI, diabetes, previous cardiovascular diseases, smoking status, genetic variants, inflammatory status, microenvironment (including microbiota and DNA methylation status), and risk factors for susceptibility to bleeding.

The ADD-Aspirin randomized trial [26] is ongoing and will allow achieving information on the aspirin dose to prevent recurrence and survival for colorectal, gastro-esophageal, breast, and prostate cancer. This is a three arms study for individuals <75 years (placebo, 100 mg, or 300 mg daily aspirin), and only two arms (placebo or 100 mg daily aspirin) for subjects ≥75 years old. The open-label run-in data, available for 2253 participants, are encouraging: grade 1–2 dyspepsia was the most frequent adverse event (11%), and only 0.5% of grade 3 side effects were reported.

reference link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8952565/


More information: Yifan Wang et al, Aspirin’s effect on kinetic parameters of cells contributes to its role in reducing incidence of advanced colorectal adenomas, shown by a multiscale computational study, eLife (2022). DOI: 10.7554/eLife.71953

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