Potatoes for Targeting Colon Cancer Stem Cells
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Colon cancer kills over 600,000 people annually worldwide. Unfortunately, current colon cancer prevention strategies like non-steroidal anti-inflammatory drugs (e.g., aspirin) can lead to serious adverse side effects such as intestinal bleeding. However, fruit and vegetable consumption has been associated with up to a 40% decrease in colon cancer risk. The benefits of a diet high in fruits and vegetables could be partly attributed to the bioactive components such as the fiber, resistant starch and polyphenolics present in them. Given that cancer incidence is expected to rise by about 70% over the next two decades, there is a critical need to develop staple foods that fight colon cancer. We recently reported that colored flesh potatoes that contain both resistant starch and polyphenols can target cancer stem cells. Thus, there is an opportunity to develop a staple food crop approach to targeting the growing epidemic of cancer globally.
KeywordsPotato Starch Phenolic acids Flavonoids Anthocyanins Cancer stem cells Cancer prevention Colon cancer
El cáncer de colon mata sobre 600,000 personas anualmente en el mundo. Desafortunadamente, las estrategias actuales de prevención de este cáncer, como las drogas no-esteroidales antiinflamatorias (p ej aspirina) pudieran conducir a efectos secundarios serios adversos, como el sangrado intestinal. No obstante, el consumo de frutas y verduras se ha asociado hasta con un 40% de disminución en el riesgo de contraer cáncer de colon. Los beneficios de una dieta alta en frutas y verduras pudieran atribuirse parcialmente a los componentes bioactivos tales como la fibra, almidón resistente y polifenoles presentes en ellas. Si damos por hecho que se espera que aumente la incidencia del cáncer como un 70% en las próximas dos décadas, hay una necesidad crítica de desarrollar alimentos básicos que combatan a dicho cáncer. Recientemente reportamos que la papa con pulpa pigmentada que contiene almidón resistente y polifenoles puede acertarle a las células basales del cáncer. De aquí que haya una oportunidad de desarrollar una estrategia de cultivo de alimento básico dirigida a la creciente epidemia global del cáncer.
Why is the Colon Susceptible to Cancer Development and What are the Risk Factors?
The human colon is a layered structure that includes an epithelial layer. Columnar epithelial cells are folded into finger-like invaginations to form colon crypts, the functional units of the colon (Barker et al. 2007; Blanpain et al. 2007). These colon crypts increase the surface area for absorption of water and minerals. Old colon epithelial cells are sloughed off into the lumen of the colon or undergo programmed cell death; cells of the colonic epithelium are renewed every 3–5 days (Blanpain et al. 2007). These rapidly multiplying epithelial cells are more vulnerable to environmental and food toxicants as well as gut bacteria-produced genotoxins, thus elevating risk for colon cancer (Center et al. 2009). Emerging evidence suggests that dysregulation of stem cell signaling pathways due to mutations and epigenetic changes drives the development of cancer (Sell 2010).
Environmental factors such as excessive alcohol consumption, smoking, obesity, lack of physical activity and a high-fat diet are responsible for approximately 80% of colon cancers (Center et al. 2009; Ferrari et al. 2007). Genetic conditions are largely responsible for the other 20% (Winawer et al. 1996). Environmental and genetic factors contribute to dysregulation of stem cell signaling pathways, and ultimately to the development of tumors. Chronic low-grade inflammation drives the dysregulation of colon stem cell kinetics, making those who suffer from inflammatory bowel diseases at greater risk of developing colon cancer (Kim and Chang 2014; Sebastian et al. 2014). Most colon cancer cases are diagnosed after 50 years of age, suggesting that age also is a risk factor. Compared to Caucasian populations, African American populations are at greater risk for colon cancer (Winawer et al. 1996). Thus, environmental factors and genetics, as well as their interaction, may contribute to colon cancer susceptibility.
Problems with Current Colon Cancer Prevention and Treatment Strategies
Few medical options to prevent or treat colon cancer are without harmful side effects. Currently, daily intake of low-dose aspirin is recommended for adults who are at greater risk for colon cancer. However, regular aspirin use can lead to stomach bleeding. Cancer stem cells (CSCs) possess more robust protective mechanisms compared to non-CSCs (Lin et al. 2013; Garza-Treviño et al. 2015) and are responsible for tumor recurrence following chemotherapy. Chemotherapeutic agents commonly used to treat colon cancer are not effective against CSCs; CSCs have a characteristically low proliferation rate compared to non-CSCs (Visvader and Lindeman 2008; Beck and Blanpain 2013; Yan and Tang 2014).
In addition to a lower proliferation rate, CSCs include cellular pumps that efficiently remove chemotherapeutics (Wang et al. 2016) before they can arrest cell proliferation or induce apoptosis. While radiation therapy is not typical for colon cancer, CSCs resist even radiation-induced apoptosis or programmed cell death (Skvortsova et al. 2015; Clark and Palle 2016). Failure to target the CSCs that are the root of colon tumor development leads to chemotherapy resistance and recurrence.
Can Plant Foods/Components Target Cancer Stem Cells?
There is a growing interest in foods and food components that can efficiently target cancer stem cells. It has been suggested that the anti-inflammatory activity of curry is one of the reasons for low colon cancer incidence in India, where it has been used as an excellent source of anti-inflammatory components for thousands of years. Quercetin, a flavonoid found in berries, capers, and onions can target colon cancer stem cells at concentrations of 75 μM or more (Atashpour et al. 2015). Piperine, an alkaloid present in black pepper, induced cell cycle arrest, endoplasmic reticulum stress, and apoptosis in certain colon cancer cells. It further suppressed the self-renewal and sphere formation ability of colon cancer cells in vitro, suggesting that piperine can potentially target colon CSCs (Samykutty et al. 2013).
The pathways involved in the chronic inflammation that prevent wounds from healing have been shown to elevate cancer stem cell populations. Several reports have suggested that anthocyanins, a class of flavonoids, are useful in wound healing (Nizamutdinova et al. 2009; Xu et al. 2013) and may possess anti-cancer activity (Reddivari et al. 2007b). Studies that have emphasized only one dietary component have not worked well in humans (Alberts et al. 2000; Goodman et al. 2004). However, whole foods such as berries that contain an array of active ingredients such as fiber and polyphenols seem to support anti-proliferative activity of cancer cells (Stoner 2009; Stoner et al. 2010). There is growing interest in staple crops containing fiber or fermentable resistant starch and phytochemicals to target the multiple pathways that support colon CSC survival.
Why Potatoes for Targeting Colon Cancer Stem Cells?
Potatoes are a good source of phytochemicals with anti-cancer activity, including phenolic acids and flavonoids (Navarre et al. 2016). The polyphenolic content of potato ranges from 530 to 1770 μg/g fresh weight (Reddivari et al. 2007b). White potatoes are an excellent source of phenolic acids including caffeic acid, chlorogenic acid, and ferulic acid. Interestingly, phenolic acids are present at amounts 5–12 times greater in purple-fleshed potatoes compared to their white-fleshed counterparts. Red- and purple-pigmented varieties also contain anthocyanins, a class of flavonoids, along with phenolic acids. Purple-fleshed cultivars are known to exhibit as much as ten times more antioxidant activity than white-fleshed potatoes (Madiwale et al. 2012). The major anthocyanins identified were coumaryl–rutino–glucosides of petunidin, peonidin, malvidin and pelargonidin (Reddivari et al. 2007a). Though estimated anthocyanin intake in the United States is between 180 and 215 mg/d, the systemic levels of anthocyanins are low compared to colonic levels because of poor bioavailability (Hidalgo et al. 2012; Valenti et al. 2013). Growing evidence suggests that there is a reciprocal interaction between anthocyanins and gut bacteria (Hidalgo et al. 2012). Anthocyanins elevate beneficial gut bacterial abundance. Gut bacterial anthocyanin metabolites more effectively suppress a key regulator of chronic intestinal inflammation and colon carcinogenesis than the parent anthocyanins (Sido et al. 2017; Amini et al. 2018). We have shown that pigs consuming a purple potato-supplemented (10% w/w) diet expressed one-sixth the chronic intestinal inflammatory agent as pigs on a high-fat control diet (Sido et al. 2017). Similar effects were observed whether potatoes were uncooked or baked. Because chronic inflammation has been associated with colon cancer, these results also support the assertion that a food-based approach could improve intestinal wound healing, and thus suppress colon tumor development. The pathways involved in chronic inflammation create an environment conducive to wound persistence and elevate cancer stem cell populations (Arwert et al. 2012; Ge et al. 2017). Suppression of these pathways by consumption of anthocyanin-containing plant foods is essential (Kaspar et al. 2011). It is not clear whether white-fleshed potatoes exert similar effects as pigmented potatoes; white potatoes can elevate intestinal anti-inflammatory butyric acid and deliver phenolic acids but not anthocyanins.
We further studied the relationship between potato anthocyanins and the suppression of human colon cancer cell proliferation and promotion of apoptosis. We previously reported that anthocyanin-containing purple potato extracts, even after baking, suppressed proliferation and induced apoptosis in vitro similar to raw purple-fleshed potato extracts, in colon cancer cell lines (Madiwale et al. 2011, 2012). We further showed that baked purple-fleshed potato extracts at a dosage of 5.0 μg/mL can suppress not only proliferation but also induce apoptosis in human colon cancer stem cells (Charepalli et al. 2014).
Considering that colored-flesh potatoes can target colon cancer stem cells in vitro and can elevate butyric acid in the colon as well as potent anti-inflammatory and anti-proliferative gut bacterial anthocyanins metabolites, we studied anti-colon cancer stem cell activity in vivo. For this study, we used baked purple-fleshed potato (20% w/w) and a well-established chemically-induced mouse model of colon tumor development. A purple-fleshed potato diet was as effective as sulindac, an experimental drug that targets colon cancer stem cells in vivo; sulindac but the drug has serious adverse side effects. Purple potato extracts reduced the number of crypts containing cells that are indicators of colon CSCs (Charepalli et al. 2015). Thus, our data suggest that purple potato extracts may reduce the number of colon CSCs and tumors in vivo.
We are preparing for a clinical study to determine whether colored-flesh potatoes could target human colon cancer stem cells in humans. However, unlike a pill, potatoes contain a variety of components and their content and composition changes with storage conditions and preparation. Moreover, recent studies revealed that colored-flesh potatoes differ significantly among cultivars in the pattern of anthocyanin release and breakdown during digestion. Their effect on colon cancer vs. healthy colon cells differ as well (Kubow et al. 2017). Purple potato exhibited antimicrobial activity against pathogenic gut bacteria (Bacillus cereus, Escherichia coli and Pseudomonas aeruginosa) only after simulated gastrointestinal digestion, but not directly in raw and cooked states, indicating that metabolism of potato by gut bacteria is critical for its anti-bacterial activity (Ombra et al. 2015). For this new knowledge to improve human health world-wide, systematic supply-chain operations to improve or retain the anti-inflammatory, anti-microbial and anti-cancer activity of potatoes are needed (Vanamala 2017). Advancements in analytical techniques such as metabolomics and big data tools (Markam et al. 2014; Charepalli et al. 2016) that can help in consistently delivering health-benefiting food components and our ability to detect cancer stem cells provide a unique opportunity to harness the anti-cancer activity of staple crops.
Jairam K. P. Vanamala was the PI of the National Research Interest Integrated Grant 2009-55200-05197 from USDA-NIFA that supported the work. Thanks to Dr. Lavanya Reddivari for feedback and Linda J Brewer for valuable edits.
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