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Racial disparity in colorectal cancer: Gut microbiome and cancer stem cells

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World Journal of Stem Cells 2016年第9期8卷 279-287页

作者： Sachin Goyal Pratima Nangia-Makke Lulu Farhana Yingjie Yu adhip pn majumdar Department of Internal Medicine John D Dingell VA Medical Center Detroit MI 48201 United States Department of Internal Medicine Wayne State University Detroit MI 48201 United States Karmanos Cancer Institute Wayne State University School of Medicine Detroit MI 48201 United States

Over the past two decades there has been remarkable progress in cancer diagnosis, treatment and screening. The basic mechanisms leading to pathogenesis of various types of cancers are also understood better and some patients, if diagnosed at a particular stage go on to lead a normal pre-diagnosis life. Despite these achievements, racial disparity in some cancers remains a mystery. The higher incidence, aggressiveness and mortality of breast, prostate and colorectal cancers(CRCs) in AfricanAmericans as compared to Caucasian-Americans are now well documented. The polyp-carcinoma sequence in CRC and easy access to colonic epithelia or colonic epithelial cells through colonoscopy/colonic effluent provides the opportunity to study colonic stem cells early in course of natural history of the disease. With the advent of metagenomic sequencing, uncultivable organisms can now be identified in stool and their numbers correlated with the effects on colonic epithelia. It would be expected that these techniques would revolutionize our understanding of the racial disparity in CRC and pave a way for the same in other cancers as well. Unfortunately, this has not happened. Our understanding of the underlying factors responsible in African-Americans for higher incidence and mortality from colorectal carcinoma remains minimal. In this review, we aim to summarize the available data on role of microbiome and cancer stem cells in racial disparity in CRC. This will provide a platform for further research on this topic.

关键词： Colorectal cancer Cancer stem cells Racial disparity Microbiome MiRNA

Gut microbiome profiling and colorectal cancer in African Americans and Caucasian Americans

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World Journal of Gastrointestinal Pathophysiology 2018年第2期9卷 47-58页

作者： Lulu Farhana Fadi Antaki Farhan Murshed Hamidah Mahmud Stephanie L Judd Pratima Nangia-Makker Edi Levi Yingjie Yu adhip pn majumdar Department of Internal Medicine John D Dingell Veterans Affairs Medical Center Department of Internal Medicine Wayne State University School of Medicine Division of Gastroenterology John D Dingell VA Medical Center Department of Medicine Karmanos Cancer Institute Department of Pathology Service John D Dingell VA Medical Center

AIM To determine whether and to what extent the gut microbiome is involved in regulating racial disparity in colorectal cancer(CRC). METHODS All patients were recruited and experiments were performed in accordance with the relevant guidelines and regulations by the Institutional Review Boards (IRB), committees of the John D. Dingell VAMC and Wayne State University guidelines. African American (AA) and Caucasian American (CA) patients were scheduled for an outpatient screening for colonoscopy, and no active malignancy volunteer patients were doubly consented, initially by the gastroenterologist and later by the study coordinator, for participation in the study. The gut microbial communities in colonic effluents from AAs and CAs were examined using 16 sRNA profiling, and bacterial identifications were validated by performing SYBR-based Real Time PCR. For metagenomic analysis to characterize the microbial communities, multiple software/tools were used, including Metastats and R statistical software.RESULTS It is generally accepted that the incidence and mortality of CRC is higher in AAs than in CAs. However, the reason for this disparity is not well understood. We hypothesize that the gut microbiome plays a role in regulating this disparity. Indeed, we found significant differences in species richness and diversity between AAs and CAs. Bacteroidetes was more abundant in AAs than in CAs. In particular, the pro-inflammatory bacteria Fusobacterium nucleatum and Enterobacter species were significantly higher in AAs, whereas probiotic Akkermansia muciniphila and Bifidobacterium were higher in CAs. The polyphyletic Clostridia class showed a divergent pattern, with Clostridium XI elevated in AAs, and Clostridium IV, known for its beneficial function, higher in CAs. Lastly, the AA group had decreased microbial diversity overall in comparison to the CA group. In summary, there were significant differences in pro-inflammatory bacteria and microbial diversity between AA and CA, which may help explain the CRC disparity between

关键词： Human gut Microbiome Colorectal cancer Fusobacterium nucleatum African Americans 16S RNA profiling Metagenomics

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结肠癌复发的规定和治疗学的策略的开发

World Journal of Gastrointestinal Pathophysiology 2012年第1期3卷 1-9页

作者： Shailender Singh Kanwar Anuradha Poolla adhip pn majumdar Veterans Affairs Medical Center Department of Internal Medicine Karmanos Cancer Institute Wayne State University-School of Medicine Detroit MI 48201 United States

Recurrence of colon cancer still remains a major issue which affects nearly 50% of patients treated by conventional therapeutics. Although the underlying causative factor(s) is not fully understood, development of drug-resistance has been associated with induction of cancer stem or stem-like cells (CSCs) which constitute a small sub-population of tumor cells known to be highly resistant to chemotherapy. In fact, the discovery of CSCs in a variety of tumors (including colon cancer) has changed the view of carcinogenesis and therapeutic strategies. Emerging reports have indicated that to improve patient outcomes, conventional anticancer therapies should be replaced with specifi c approaches targeting CSCs. Thus, therapeutic strategies that specifically target CSCs are being sought to reduce the risk of relapse and metastasis. In order to specifi cally target colon CSCs (while sparing somatic intestinal stem cells), it is critical to identify unique deregulated pathways responsible for self-renewal of CSCs and colon cancer recurrence. Colon CSCs present a unique opportunity to better understand the biology of solid tumors. Thus, a better understanding of the clinical signs and symptoms of colon cancer patients (under-going surgery or chemotherapy) during perioperative periods, along with the underlying regulatory events affecting the stem/progenitor cell self-renewal and differentiation of colon epithelial cells, is of immense importance. In this review we discuss the implication of clinical factors and the emerging role of CSCs during recurrence of colon cancer along with the development of new therapeutic strategies involving the use of natural agents.

关键词： Chemo-resistance 5-Fluorouracil Oxaliplatin β-catenin Cancer stem cells

Folic acid supplementation inhibits recurrence of colorectal adenomas:A randomized chemoprevention trial

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World Journal of Gastroenterology 2008年第28期14卷 4492-4498页

作者： Richard Jaszewski Sabeena Misra Martin Tobi Nadeem Ullah Jo Ann Naumoff Omer Kucuk Edi Levi Bradley N Axelrod Bhaumik B Patel adhip pn majumdar John D Dingell Veterans Affairs Medical Center Karmanos Cancer InstituteDepartment of Internal MedicineWayne State University School of MedicineDetroitMI 48201United States

AIM: To determine whether folic acid supplementation will reduce the recurrence of colorectal adenomas, the precursors of colorectal cancer, we performed a double-blind placebo-controlled trial in patients with adenomatous polyps. METHODS: In the current double-blind, placebo-controlled trial at this VA Medical Center, patients with colorectal adenomas were randomly assigned to receive either a daily 5 mg dose of folic acid or a matched identical placebo for 3 years. All polyps were removed at baseline colonoscopy and each patient had a follow up colonoscopy at 3 years. The primary endpoint was a reduction in the number of recurrent adenomas at 3 years. RESULTS: Of 137 subjects, who were eligible after confirmation of polyp histology and run-in period to conform compliance, 94 completed the study; 49 in folic acid group and 45 in placebo group. Recurrence of adenomas at 3-year was compared between the two groups. The mean number of recurrent polyps at 3-year was 0.36 (SD, 0.69) for folic acid treated patients compared to 0.82 (SD, 1.17) for placebo treated subjects, resulting in a 3-fold increase in polyp recurrence in the placebo group. Patients below 70 years of age and those with left-sided colonicadenomas or advanced adenomas responded better to folic acid supplementation. CONCLUSION: High dose folic acid supplementation is associated with a signif icant reduction in the recurrence of colonic adenomas suggesting that folic acid may be an effective chemopreventive agent for colorectal neoplasia.

关键词：结肠直肠癌腺瘤循环障碍抑制剂

Role of cancer stem cells in age-related rise in colorectal cancer

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World Journal of Gastrointestinal Pathophysiology 2015年第4期6卷 86-89页

作者： Pratima Nangia-Makker Yingjie Yu adhip pn majumdar Veterans Affairs Medical Center Department of Internal MedicineKarmanos Cancer InstituteWayne State UniversitySchool of MedicineResearch Service

Colorectal cancer(CRC) that comprises about 50% of estimated gastrointestinal cancers remains a high mortality malignancy. It is estimated that CRC will result in 9% of all cancer related deaths. CRC is the third leading malignancy affecting both males and females equally; with 9% of the estimated new cancer cases and 9% cancer related deaths. Sporadic CRC, whose incidence increases markedly with advancing age, occurs in 80%-85% patients diagnosed with CRC. Little is known about the precise biochemical mechanisms responsible for the rise in CRC with aging. However, many probable reasons for this increase have been suggested; among others they include altered carcinogen metabolism and the cumulative effects of long-term exposure to cancer-causing agents. Herein, we propose a role for self-renewing, cancer stem cells(CSCs) in regulating these cellular events. In this editorial, we have briefly described the recent work on the evolution of CSCs in gastro-intestinal track especially in the colon, and how they are involved in the age-related rise in CRC. Focus of this editorial is to provide a description of(1) CSC;(2) epigenetic and genetic mechanisms giving rise to CSCs;(3) markers of CSC;(4) characteristics; and(5) age-related increase in CSC in the colonic crypt.

关键词： Cancer stem cells Aging Colorectal cancer Colonosp

Cancer stem cells in Helicobacter pylori infection and aging: Implications for gastric carcinogenesis

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World Journal of Gastrointestinal Pathophysiology 2014年第3期5卷 366-372页

作者： Edi Levi Paula Sochacki Nabiha Khoury Bhaumik B Patel adhip pn majumdar Department of Veterans Affairs John D Dingell VA Medical Center Wayne State University Detroit MI 48201 United States Pathology Wayne State University Detroit MI 48201 United States Karmanos Cancer Center Wayne State University Detroit MI 48201 United States Departments of Internal Medicine Wayne State University Detroit MI 48201 United States

AIM: To demonstrated the combined effects of aging and carcinogen treatment on cancer stem/stem-like cells(CSCs) of gastric mucosa in an animal model. METHODS: In this study we investigated the effects of aging and Helicobacter pylori(H. pylori) inflammation as a model for inflammation induced carcinogenesis in human and rat gastric mucosa samples. In aging studies, we compared 4-mo old(young) with 22 mo(aged) old Fischer-344 rats. For human studies, gastric biop-sies and resection specimens representing normal mucosa or different stages of H. pylori gastritis and gastric adenocarcinomas were used for determining the expression of stem cell markers CD166, ALDH1 and LGR5. In addition we performed immunofluorescent double labeling for B-catenin and Lgr5 in both rat and human gastric tissues to examine the status of Wnt signaling in these cells. RESULTS: CSC markers ALDH1, LGR5, and CD166 were expressed in very low levels in normal human gastric mucosa or young rat gastric mucosa. In contrast, level of expression for all three markers significantly increased in H. pylori gastritis and gastric adenocarcinomas as well as in normal gastric mucosa in aged rats. We also observed cytoplasmic B-catenin staining in both aged rat and human H. pylori inflamed gastric mucosa, which were found to be colocalized with Lgr5 immunoreactive cells. The increased number of ALDH1, CD166 and LGR5 positive cells in H. pylori gastritis indicates that increased number of stem-like cells in gastric mucosa is an early event, and may constitute an important step in the progression to neoplasia. CONCLUSION: Our observation of the age-related increase in cancer stem/stem-like cells in the gastric mucosa may explain the increased incidence of gastric cancer during aging. Combination of aging and H. pylori infection may have additive effects in progression to neoplasia.

关键词： Cancer stem cells Aging CD166 ALDH1 LGR5 Gastric cancer Helicobacter pylori