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Role of Nut/Seed Consumption in Colorectal Cancer: History
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Contributor: Deiana Roman , Bogdan Timar , Vlad Avram , Adina Braha , Sorin Saftescu , Șerban Negru , Romulus Timar

Diet is an important factor that influences the incidence of colorectal cancer, with red meat consumption in particular being associated with a higher risk of colorectal cancer, while higher consumption of fruits and vegetables, as seen in the Mediterranean diet, seems to have protective effects. Among the food categories, nuts and seeds boast numerous beneficial effects for cardiovascular health and metabolic balance and they contain a plethora of phytochemicals and antioxidants.

  • colorectal cancer
  • dietary habits
  • nuts
  • seeds

1. Introduction

Colorectal cancer incidence is among the highest in the world, with higher incidences being noted in countries transitioning towards higher economic status [1], implying that the socioeconomic shifts that occur during the development of a country have a profound influence on that society’s health, leading some to imply that colon cancer incidence is a sign of socioeconomic development [2].

Regarding treatment, it seems that lifestyle factors influence outcomes beyond the effects of chemotherapy and surgical interventions [3][4]. To date, increased patient BMI, a western type of dietary pattern and increased glycaemic load in patient diet have been associated with higher recurrence rates and increased mortality in stage III colorectal cancer, while physical exercise, a healthy Nordic diet or Mediterranean diet have shown protective effects [3][4][5][6].

The hallmarks of the Mediterranean diet are high fibre content derived from whole grains, protein and unsaturated fat, mostly based on fish-derived polyunsaturated fatty acids, associated with decreased content of saturated fats [7]. Furthermore, multiple servings of fruits and vegetables have also proven to be a beneficial attribute of this diet, with particular emphasis on the consumption of nuts [7].
Nuts have been a subject of increasing focus in regard to the improvement of overall health and mortality reduction in various diseases [8][9][10]. Apart from the well-known role that they have in reducing the incidence and mortality of cardiovascular diseases [7][11], there is an increasing body of evidence suggesting that nuts might aid in the prevention of cancer [12]. Nuts possess anticarcinogenic and antioxidant properties due to their content of tocopherols, phytosterols, folic acid and certain minerals, such as selenium or magnesium [13]. Polyphenols such as ellagitannins and urolithins, present in nuts, add to their anticancer properties, although the exact mechanisms of action are still under research and debate [14]. These compounds have been known to inhibit cancer cell proliferation, in colon cancer specifically, in a dose-dependent manner [15]. The phytochemicals found in nuts can behave in one of two ways, either inhibiting tumour initiation by acting as blocking agents (ellagic acid, flavonoids, indole-3-carbinol), or by halting tumour progression by acting as suppressing agents (betacarotene, resveratrol, inositol pentakiphosphate, inositol hexakisphosphate) [16]. Another possible mechanism that contributes to the benefits that nuts present in regard to colon cancer would be that nut consumption induces changes in the microbiota, which in turn modulate cell signalling and key cellular processes in the aspect of protein kinase signalling [14].
Although nuts in general are seen to have beneficial effects on health, there are differences in the magnitude or the effect itself that varies with each specific nut, which is not surprising seeing as nut composition varies within each nut type [8].

2. Role of Nut/Seed Consumption in Colorectal Cancer

One of the earliest studies that included nut consumption in the recorded research items was ″The Nurses’ Health Study″ that was initiated in 1976 and that enrolled female nurses in the US, aged between 30 and 55 [17]. Published in 2016, the study prospectively followed approximately 76,000 women, and during the follow-up period, 1503 colorectal cancer cases were identified. At baseline, all participants had been cancer-free. In patients that reported a colorectal cancer diagnosis, permission to access medical records was requested [17].
Participants were asked to respond to a semiquantitative food frequency questionnaire. In 1980 and 1984, this questionnaire included inquiries regarding nut consumption over the preceding year: more than 6 servings a day, 4 to 6 servings a day, 2–3 servings a day, one serving a day, 5–6 servings per week, 2–4 servings per week, 1 to 3 servings per month or none/almost none. In the following questionnaires, there was a differentiation between peanuts and other nuts included, as well as a question dedicated to peanut butter consumption [17].
Consistency was maintained in regard to nut consumption throughout the study follow-up, those with higher nut consumption having a leaner body composition, being more likely to exercise, to take more multivitamin supplements, to consume more fruit and vegetables, as well as fibre, folate and calcium, being less likely to smoke, but more inclined to consume alcohol, as well as more likely to have lower endoscopy performed [17].
Consecutive to adjusting for other well-known or suspected risk factors for colorectal cancer, results showed that those female participants who consumed nuts with a frequency of two or more times per week, meaning more than or equal to 56 g of nuts per week, showed a decrease in colorectal cancer risk when compared to those with no or lower nut consumption, without reaching the threshold for statistical significance (RR: 0.87; 95% CI: 0.72–1.05; Ptrend: 0.06). For peanut butter in particular, there was no association to be observed in the studied group of participants [17].
The European Prospective Investigation into Cancer and Nutrition (EPIC) published in 2004 included 10 European countries and was designed as a prospective cohort study. Within this larger body of research, a series of questions focused on the nut and seed intake of participants in relation to colorectal cancer risk [18]. The total nut and seed intake of participants was determined using a dietary questionnaire validated for all populations involved in the study. It is one of the largest, if not the largest, prospective cohort studies conducted investigating the link between diet and cancer [18]. The results for the combined genders showed no notable protective association between nut and seed intake and the risk of colorectal cancer, whereas, upon subgroup analysis by participant gender, it was revealed that even an intake as modest as 16 g of nuts and seeds per day is associated with a reduced incidence of colorectal cancer (HR, 0.69; 95% CI, 0.50–0.95; fully adjusted model), particularly distal colon cancer (HR, 0.52; 95% CI, 0.32–0.85; fully adjusted model), in those women compared to those who did not consume nuts and seeds. This, however, does not apply to the male gender, though the reason for this disparity remains unclear and is to be further investigated [18].
Among researchs focusing on the incidence of new cancer cases in regard to nut consumption in participants without cancer at baseline, there also are studies that have researched the impact that the consumption of nuts has on patients with diagnosed colon cancer, such as a research that included 826 patients with stage III colon cancer that completed food frequency questionnaires including 131 foodstuffs and vitamin and mineral supplements, while also leaving an open-ended section to be completed with other items that might not have been included in the questionnaire. Participants were questioned regarding the frequency of consumption of different items (in their respective portion sizes) over the previous three months, with nine possible answers, ranging from never to 6+ times per day. The median follow-up time was 6.5 years [19].
While the existing research is divided between those studies which have found no significant link between nut consumption and colorectal cancer protection and those which have, there is a consensus regarding the necessity for further research on this subject, as well as the possible mechanisms which might be involved in the protective effect observed by some researchers.
Researchers have identified four major phenolic compounds in the walnut phenolic extract (WPE), namely gallic acid, catechin, chlorogenic acid and ellagic acid in various quantities, catechin being the most abundant, followed by chlorogenic acid, ellagic acids and, lastly, gallic acid [20].
CD133+, CD44+, and HCT116 cells were treated with WPE for 2,4 and 6 days, showing a suppression of cell growth in a manner that was dose-dependent. In particular, 40 μg/mL WPE was shown to inhibit cell growth by up to 34.4% (p < 0.01) after 2 days, 59.1% (p < 0.001) after 4 days and 85.8% (p < 0.01) after 6 days when compared to control cells. Consecutively, it was determined that WPE extract showed the highest efficacy at 4 and 6 days, while its individual bioactive compounds were not found to have significantly different effects on cell growth after 4 and 6 days of treatment [20].
mRNA levels of established cancer stem cell (CSC) markers including CD133, CD44, DLK1 and Notch1 underwent RT-PCR investigation, revealing suppression of their expression by WPE in a manner that was dose-dependent. Furthermore, comparable dosages of the bioactive compounds equivalent to 40 μg/mL WPE also proved highly effective in the suppression of the four CSC markers. By comparison, though, WPE was found to be superior to the individual bioactive compounds in regard to the down-regulation of the expression of these CRC markers [20].
WPE was also shown to suppress the self-renewal capacity of colon CSC through the observation of single cells and their ability to form a colony. When CD133+, CD44+ and HCT116 cells underwent treatment with WPE in various concentrations, the number of cells that were able to form colonies showed a decrease in a dose-dependent manner, up to 94%. Again, WPE as a whole compared to each individual bioactive component showed superior efficacy in the colony formation suppression [20].
Sphere formation has also been shown to decrease in a dose-dependent fashion, cells treated with WPE having an inferior capacity to form spheres, this suppression rising to 72.3%, compared to non-treated cells, indicating that WPE as well as its bioactive compounds are able to suppress CSC by regulating self-renewal capacity [20].
In order to confirm the applicability of these findings in the human CRC tissue, primary cells from this tissue were isolated and received treatment with WPE in varying doses, with results showing a significant down-regulation in mRNA levels of CD133+ markers by 62%, of CD44+ markers by 33.5%, of DLK1 markers by 57.1% and of Notch1 markers by 81.1% compared to control cells [20].
Phytosterols have cholesterol-lowering effects that have beneficial anticarcinogenic effects beyond the well-known cardiovascular benefits [21]. Lower cholesterol levels have proven beneficial in lowering cancer progression, migration and invasion, modifying various tumor-generating pathways such as modifying VEGF expression, influencing LDL-receptors, decreasing the expression of Niemann–Pick C1-like 1 transporter and reducing reactive oxygen species [21][22]. There is also evidence of the contribution of phytosterols to reducing cancer risk by means of their anti-inflammatory properties, such as decreasing nuclear translocation of nuclear factor kappa B [21]. Further anticancer properties of phytosterols may be through their activation of AMP-kinase, an enzyme that is also activated by metformin, which has been long known to have beneficial effects regarding cancer [21][23]. Moreover, they have been found to increase interleukin 2 and interferon-γ, possibly limiting tumor metastasis [21].

3. Conclusions

Nut and seed consumption has shown multiple benefits for the health of individuals; nowadays, the scientific community poses an intriguing and important question regarding its effect in cancer, particularly colorectal cancer. In the attempt to answer this question, multiple studies have been conducted, leading to often contradicting results. The study design, selected population, patient clinical status, self-declared nut intake, memory bias and a host of other inconsistencies might be at the root of these discrepancies. Knowledge to date infers possible mechanisms through which nuts and seeds could influence the development and progression of colorectal cancer, underlining the need for further research in this particular domain.

This entry is adapted from the peer-reviewed paper 10.3390/medicina58070932

References

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