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Pathogenesis and Prevention of Colorectal Cancer

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (15 July 2013) | Viewed by 114235

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Special Issue Editors

Prof. Dr. Christoph Gasche

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Guest Editor

Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria
Interests: colorectal cancer; colitis associated cancer; cancer chemoprevention; DNA damage response; genetic instability; inflammatory bowel diseases; iron and colorectal cancer; iron deficient megakaryopoiesis; IL-10 signaling; mucosal immunology; mesalamine; microsatellite instability; natural compounds; P-21-activated kinase-1; endoscopy; iron therapy

Dr. Vineeta Khare

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Co-Guest Editor

Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, A-1090, Vienna, Austria
Interests: colorectal cancer; colitis associated cancer; cancer chemoprevention; DNA damage response; genetic instability; inflammatory bowel diseases; iron and colorectal cancer; iron deficient megakaryopoiesis; IL-10 signaling; mucosal immunology; mesalamine; microsatellite instability; natural compounds; P-21-activated kinase-1

Special Issue Information

Dear Colleagues,

Colorectal cancer is one of the leading causes of mortality in the western world. A better understanding of the pathogenesis of colorectal cancer will help to improve preventive measures and thereby reduce cancer incidence. While there is not just a single cause predisposing to cancer; intestinal polyps, genetic syndromes (FAP, HNPCC), chronic inflammation (such as IBD), diet and lifestyle; all impose risk to the pathogenesis and development of colorectal cancer.

We invite investigators working in the field of pathogenesis and prevention of colorectal cancer, to submit original papers or reviews highlighting the epidemiology, pathogenesis, management and prevention of colorectal carcinogenesis to further enhance our understanding of the state of art in this field. The topics of interest could include, but are not limited to:

Somatic and genetic determinants in derangement of intestinal homeostasis
Role of inflammation in initiation and progression of colorectal cancer
Hereditary cancer syndromes
Phenotypic and molecular presentation of the disease
Mechanistic studies on colorectal carcinogenesis
Prognostic and predictive biomarkers reflecting qualitative and quantitative disease activity, progression of cancer and prediction of the outcome of the treatment
The rationale of prevention and interruption of colorectal carcinogenesis
Prospects for new preventive strategies including dietary or lifestyle changes, nutritional supplements, natural compounds or pharmaceuticals

Prof. Dr. Christoph Gasche
Dr. Vineeta Khare
Guest Editors

Submission

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed Open Access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1600 CHF.

Keywords

colorectal cancer
colitis-associated cancer
hereditary cancer syndromes
chemoprevention
biomarker
microsatellite instability
chromosomal instability
CpG island methylator phenotype
polyp
DNA repair

Published Papers (14 papers)

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Research

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546 KiB

Open AccessArticle

Pro-Apoptotic Effect of Rice Bran Inositol Hexaphosphate (IP₆) on HT-29 Colorectal Cancer Cells

by Nurul Husna Shafie, Norhaizan Mohd Esa, Hairuszah Ithnin, Norazalina Saad and Ashok Kumar Pandurangan

Int. J. Mol. Sci. 2013, 14(12), 23545-23558; https://doi.org/10.3390/ijms141223545 - 02 Dec 2013

Cited by 27 | Viewed by 8200

Abstract

Inositol hexaphosphate (IP₆), or phytic acid is a natural dietary ingredient and has been described as a “natural cancer fighter”, being an essential component of nutritional diets. The marked anti-cancer effect of IP₆ has resulted in our quest for an understanding of its mechanism of action. In particular, our data provided strong evidence for the induction of apoptotic cell death, which may be attributable to the up-regulation of Bax and down-regulation of Bcl-xl in favor of apoptosis. In addition, the up-regulation of caspase-3 and -8 expression and activation of both caspases may also contribute to the apoptotic cell death of human colorectal adenocarcinoma HT-29 cells when exposed to IP₆. Collectively, this present study has shown that rice bran IP₆ induces apoptosis, by regulating the pro- and anti-apoptotic markers; Bax and Bcl-xl and via the activation of caspase molecules (caspase-3 and -8). Full article

(This article belongs to the Special Issue Pathogenesis and Prevention of Colorectal Cancer)

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Open AccessArticle

Defective Generation and Maturation of Dendritic Cells from Monocytes in Colorectal Cancer Patients during the Course of Disease

by Giulia Orsini, Annalisa Legitimo, Alessandra Failli, Paola Ferrari, Andrea Nicolini, Roberto Spisni, Paolo Miccoli and Rita Consolini

Int. J. Mol. Sci. 2013, 14(11), 22022-22041; https://doi.org/10.3390/ijms141122022 - 07 Nov 2013

Cited by 38 | Viewed by 6768

Abstract

Colorectal cancer (CRC) is the second-leading cause of cancer-related deaths in Western countries. Today, the role of the host’s immune system in controlling the progression and spread of solid tumors is broadly established. Tumor immunosurveillance escape mechanisms, such as those involving dendritic cells (DCs), the most important antigen-presenting cells, are likewise recognized processes involved in cancer. The present study evaluates the ability of CRC patients to generate DCs in vitro from circulating monocytes at both pre- and post-operative timepoints; the results are correlated with the stage of disease to shed light on the systemic immune statuses of CRC patients. Our data showed that patients’ DCs had lower co-stimulatory molecule expression and were less able to present antigens to allogeneic T cells compared to healthy controls’ (HC) DCs. Furthermore altered cytokine secretion, such as increased IL-10 and reduced IL-12 and TNF-α, was observed. At the post-operative timepoints we observed a recovery of the patients’ ability to generate immature DCs, compared to HCs, but the maturational capacity remained affected. Our study conclusively highlights the persistently impaired in vitro generation of fully mature and functional DCs, which appears to be more altered during advanced stages. This work sheds light on a dendritic cell-based tumor immune escape mechanism that could be useful for the development of more effective immunotherapeutic strategies. Full article

(This article belongs to the Special Issue Pathogenesis and Prevention of Colorectal Cancer)

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Open AccessArticle

Significant Overexpression of DVL1 in Taiwanese Colorectal Cancer Patients with Liver Metastasis

by Ming-Yii Huang, Li-Chen Yen, Hsueh-Chiao Liu, Po-Ping Liu, Fu-Yen Chung, Tsu-Nai Wang, Jaw-Yuan Wang and Shiu-Ru Lin

Int. J. Mol. Sci. 2013, 14(10), 20492-20507; https://doi.org/10.3390/ijms141020492 - 14 Oct 2013

Cited by 14 | Viewed by 6213

Abstract

Undetected micrometastasis plays a key role in the metastasis of cancer in colorectal cancer (CRC) patients. The aim of this study is to identify a biomarker of CRC patients with liver metastasis through the detection of circulating tumor cells (CTCs). Microarray and bioinformatics analysis of 10 CRC cancer tissue specimens compared with normal adjacent tissues revealed that 31 genes were up-regulated (gene expression ratio of cancer tissue to paired normal tissue > 2) in the cancer patients. We used a weighted enzymatic chip array (WEnCA) including 31 prognosis-related genes to investigate CTCs in 214 postoperative stage I–III CRC patients and to analyze the correlation between gene expression and clinico-pathological parameters. We employed the immunohistochemistry (IHC) method with polyclonal mouse antibody against DVL1 to detect DVL1 expression in 60 CRC patients. CRC liver metastasis occurred in 19.16% (41/214) of the patients. Using univariate analysis and multivariate proportional hazards regression analysis, we found that DVL1 mRNA overexpression had a significant, independent predictive value for liver metastasis in CRC patients (OR: 5.764; 95% CI: 2.588–12.837; p < 0.0001 on univariate analysis; OR: 3.768; 95% CI: 1.469–9.665; p = 0.006 on multivariate analysis). IHC staining of the immunoreactivity of DVL1 showed that DVL1 was localized in the cytoplasm of CRC cells. High expression of DVL1 was observed in 55% (33/60) of CRC tumor specimens and was associated significantly with tumor depth, perineural invasion and liver metastasis status (all p < 0.05). Our experimental results demonstrated that DVL1 is significantly overexpressed in CRC patients with liver metastasis, leading us to conclude that DVL1 could be a potential prognostic and predictive marker for CRC patients. Full article

(This article belongs to the Special Issue Pathogenesis and Prevention of Colorectal Cancer)

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Open AccessArticle

Structural Properties of Polyphenols Causing Cell Cycle Arrest at G1 Phase in HCT116 Human Colorectal Cancer Cell Lines

by Soon Young Shin, Hyuk Yoon, Seunghyun Ahn, Dong-Wook Kim, Dong-Ho Bae, Dongsoo Koh, Young Han Lee and Yoongho Lim

Int. J. Mol. Sci. 2013, 14(8), 16970-16985; https://doi.org/10.3390/ijms140816970 - 19 Aug 2013

Cited by 31 | Viewed by 8825

Abstract

Plant-derived polyphenols are being tested as chemopreventive agents; some polyphenols arrest the cell cycle at G1 phase, whereas others inhibit cell cycle proliferation at G2/M phase. Therefore, polyphenols have been proposed to inhibit cell cycle progression at different phases via distinct mechanisms. Indeed, our previous studies showed that small structural differences in polyphenols cause large differences in their biological activities; however, the details of the structural properties causing G1 cell cycle arrest remain unknown. In this study, we prepared 27 polyphenols, including eight different scaffolds, to gain insight into the structural conditions that arrest the cell cycle at G1 phase in a quantitative structure–activity relationship study. We used cell cycle profiles to determine the biophores responsible for G1 cell cycle arrest and believe that the biophores identified in this study will help design polyphenols that cause G1 cell cycle arrest. Full article

(This article belongs to the Special Issue Pathogenesis and Prevention of Colorectal Cancer)

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386 KiB

Open AccessArticle

Enhanced Development of Azoxymethane-Induced Colonic Preneoplastic Lesions in Hypertensive Rats

by Takahiro Kochi, Masahito Shimizu, Tomohiko Ohno, Atsushi Baba, Takafumi Sumi, Masaya Kubota, Yohei Shirakami, Hisashi Tsurumi, Takuji Tanaka and Hisataka Moriwaki

Int. J. Mol. Sci. 2013, 14(7), 14700-14711; https://doi.org/10.3390/ijms140714700 - 15 Jul 2013

Cited by 11 | Viewed by 6303

Abstract

Metabolic syndrome is associated with an increased risk of colorectal cancer. This study investigated the impact of hypertension, a component of metabolic syndrome, on azoxymethane (AOM)-induced colorectal carcinogenesis using SHRSP/Izm (SHRSP) non-diabetic/hypertensive rats and SHRSP.Z-Lepr^fa/IzmDmcr (SHRSP-ZF) diabetic/hypertensive rats. Male 6-week-old SHRSP, SHRSP-ZF, and control non-diabetic/normotensive Wister Kyoto/Izm (WKY) rats were given 2 weekly intraperitoneal injections of AOM (20 mg/kg body weight). Two weeks after the last injection of AOM, the SHRSP and SHRSP-ZF rats became hypertensive compared to the control WKY rats. Serum levels of angiotensin-II, the active product of the renin-angiotensin system, were elevated in both SHRSP and SHRSP-ZF rats, but only the SHRSP-ZF rats developed insulin resistance, dyslipidemia, and hyperleptinemia and exhibited an increase in adipose tissue. The development of AOM-induced colonic preneoplastic lesions and aberrant crypts foci, was significantly accelerated in both SHRSP and SHRSP-ZF hypertensive rats, compared to WKY normotensive rats. Furthermore, induction of oxidative stress and exacerbation of inflammation were observed in the colonic mucosa and systemically in SHRSP and SHRSP-ZF rats. Our findings suggest that hypertension plays a role in the early stage of colorectal carcinogenesis by inducing oxidative stress and chronic inflammation, which might be associated with activation of the renin-angiotensin system. Full article

(This article belongs to the Special Issue Pathogenesis and Prevention of Colorectal Cancer)

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Open AccessArticle

Diagnosis of Desmoplastic Reaction by Immunohistochemical Analysis, in Biopsy Specimens of Early Colorectal Carcinomas, Is Efficacious in Estimating the Depth of Invasion

by Kazuya Ohno, Takahiro Fujimori, Yosuke Okamoto, Kazuhito Ichikawa, Takeshi Yamaguchi, Johji Imura, Shigeki Tomita and Hiroyuki Mitomi

Int. J. Mol. Sci. 2013, 14(7), 13129-13136; https://doi.org/10.3390/ijms140713129 - 25 Jun 2013

Cited by 10 | Viewed by 5816

Abstract

The aim of our study was to evaluate the diagnosis of desmoplastic reaction (DR) by immunostaining for α-smooth muscle actin (αSMA) and desmin, for predicting the depth of submucosal invasion in biopsy specimens of early colorectal carcinomas (CRCs). Thirty-eight cases of non-pedunculated early CRCs were included in this study. Positive for DR was defined as αSMA-positive and desmin-negative stroma in the CRC. The depth of submucosal invasion was measured in endoscopically or surgically resected specimens and the lesions were subsequently divided into two groups: Group A (carcinoma in situ/intramucosal carcinoma and submucosal invasive carcinoma with a depth <1000 μm) and Group B (submucosal invasion with a depth ≥1000 μm). Twenty-one cases were DR-positive and 17 were DR-negative. No statistical significance was found between the DR with regard to tumor size, location and histological type. All DR-positive cases belonged to Group B whereas 14 (82.4%) DR-negative lesions belonged to Group A (p < 0.001). The sensitivity, speciﬁcity, positive and negative predictive values and accuracy of DR positivity for diagnosis of Group B were 87.5%, 100%, 100%, 82.4% and 92.1%, respectively. Conclusively, detection of DR in biopsy specimens with ancillary immunohistochemistry (αSMA/desmin) would help in preoperative diagnosis for the depth of submucosal invasion of early CRC. Full article

(This article belongs to the Special Issue Pathogenesis and Prevention of Colorectal Cancer)

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202 KiB

Open AccessArticle

Polymorphisms in XPD and ERCC1 Associated with Colorectal Cancer Outcome

by Ming-Yii Huang, Jaw-Yuan Wang, Meng-Lin Huang, Hui-Jen Chang and Shiu-Ru Lin

Int. J. Mol. Sci. 2013, 14(2), 4121-4134; https://doi.org/10.3390/ijms14024121 - 19 Feb 2013

Cited by 10 | Viewed by 5779

Abstract

Using the comprehensive approach to selecting polymorphisms to date, we sought to examine whether recurrence in colorectal cancer was associated with inherited variation in three genes involved in DNA repair and cell proliferation. Three polymorphisms, which are excision repair cross-complementation 1 (ERCC1), xeroderma pigmentosum group D (XPD) and epidermal growth factor receptor (EGFR), were assessed in 257 postoperative stage II/III CRC patients with 5-fluorouracial chemotherapy in Taiwan. In addition, the correlations between genetic polymorphisms and patients’ clinicopathological features were investigated. Genotypes of XPD codon751 A/A and ERCC1 codon118 T/T were associated with regional recurrence in a statistically significant way (p = 0.018). Patients who carried XPD AA and ERCC1 TT genotypes demonstrated a significantly greater regional recurrence risk (OR = 5.625, 95% CI, 1.557–20.32). Inherited variation in XPD and ERCC1 was associated with outcome in patients with colorectal cancer in Taiwan. As the significant association of single-nucleotide polymorphisms has not been studied previously in colorectal cancer, these findings suggest novel sites of variation, in part explaining the range of treatment responses seen in this disease. Full article

(This article belongs to the Special Issue Pathogenesis and Prevention of Colorectal Cancer)

Review

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2212 KiB

Open AccessReview

The Homeobox Only Protein Homeobox (HOPX) and Colorectal Cancer

by Keishi Yamashita, Hiroshi Katoh and Masahiko Watanabe

Int. J. Mol. Sci. 2013, 14(12), 23231-23243; https://doi.org/10.3390/ijms141223231 - 25 Nov 2013

Cited by 31 | Viewed by 8328

Abstract

The HOP (homeobox only protein) homeobox (HOPX) is most closely related to the homeobox protein that contains a homeobox-like domain but lacks certain conserved residues required for DNA binding. Here, we review the current understanding of HOPX in the progression of colorectal cancer (CRC). HOPX was initially reported as a differentiation marker and is expressed in various normal tissues. In the colon, HOPX is expressed uniquely in the quiescent stem cell, +4, and in differentiated mucosal cells of the colon. HOPX expression is markedly suppressed in a subset of cancers, mainly in an epigenetic manner. CRC may include separate entities which are differentially characterized by HOPX expression from a prognostic point of view. HOPX itself can regulate epigenetics, and defective expression of HOPX can result in loss of tumor suppressive function and differentiation phenotype. These findings indicate that HOPX may be both a central regulator of epigenetic dynamics and a critical determinant for differentiation in human cells. HOPX downstream targets were identified in CRC cell lines and hold promise as candidates for therapeutic targets of CRC, such as EphA2 or AP-1. Further analysis will elucidate and confirm the precise role of such proteins in CRC progression. Full article

(This article belongs to the Special Issue Pathogenesis and Prevention of Colorectal Cancer)

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Open AccessReview

Role of cMET in the Development and Progression of Colorectal Cancer

by Juan Carlos Samamé Pérez-Vargas, Pamela Biondani, Claudia Maggi, Manuela Gariboldi, Annunziata Gloghini, Alessandro Inno, Chiara Costanza Volpi, Ambra Vittoria Gualeni, Maria Di Bartolomeo, Filippo De Braud, Alessandra Castano, Ilaria Bossi and Filippo Pietrantonio

Int. J. Mol. Sci. 2013, 14(9), 18056-18077; https://doi.org/10.3390/ijms140918056 - 03 Sep 2013

Cited by 42 | Viewed by 10288

Abstract

Mesenchymal-epithelial transition (MET) is a member of a distinct subfamily of heterodimeric receptor tyrosine kinase receptors that specifically binds the hepatocyte growth factor (HGF). Binding to HGF leads to receptor dimerization/multimerization and phosphorylation, resulting in its catalytic activation. MET activation drives the malignant progression of several tumor types, including colorectal cancer (CRC), by promoting signaling cascades that mainly result in alterations of cell motility, survival, and proliferation. MET is aberrantly activated in many human cancers through various mechanisms, including point mutations, gene amplification, transcriptional up-regulation, or ligand autocrine loops. MET promotes cell scattering, invasion, and protection from apoptosis, thereby acting as an adjuvant pro-metastatic gene for many tumor types. In CRC, MET expression confers more aggressiveness and worse clinical prognosis. With all of this rationale, inhibitors that target the HGF/MET axis with different types of response have been developed. HGF and MET are new promising targets to understand the pathogenesis of CRC and for the development of new, targeted therapies. Full article

(This article belongs to the Special Issue Pathogenesis and Prevention of Colorectal Cancer)

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Open AccessReview

Prevention of Carcinogenesis and Development of Gastric and Colon Cancers by 2-Aminophenoxazine-3-one (Phx-3): Direct and Indirect Anti-Cancer Activity of Phx-3

by Akio Tomoda, Keisuke Miyazawa and Takafumi Tabuchi

Int. J. Mol. Sci. 2013, 14(9), 17573-17583; https://doi.org/10.3390/ijms140917573 - 28 Aug 2013

Cited by 7 | Viewed by 5453

Abstract

2-Aminophenoxazine-3-one (Phx-3), an oxidative phenoxazine, exerts strong anticancer effects on various cancer cell lines originating from different organs, in vitro. This article reviews new aspects for the prevention of carcinogenesis and development of gastric and colon cancers by Phx-3, based on the strong anticancer effects of Phx-3 on gastric and colon cancer cell lines (direct anticancer effects of Phx-3 for preventing development of cancer), the bacteriocidal effects of Phx-3 against Helicobacter pylori associated with carcinogenesis of gastric cancer (indirect anticancer effects for preventing carcinogenesis of gastric cancer), and the proapoptotic activity of Phx-3 against human neutrophils involved in the incidence of ulcerative colitis associated with a high colon cancer risk (indirect anticancer effects for preventing carcinogenesis of colon cancer). Full article

(This article belongs to the Special Issue Pathogenesis and Prevention of Colorectal Cancer)

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524 KiB

Open AccessReview

Potential Targets for Colorectal Cancer Prevention

by Sally Temraz, Deborah Mukherji and Ali Shamseddine

Int. J. Mol. Sci. 2013, 14(9), 17279-17303; https://doi.org/10.3390/ijms140917279 - 22 Aug 2013

Cited by 61 | Viewed by 8731

Abstract

The step-wise development of colorectal neoplasia from adenoma to carcinoma suggests that specific interventions could delay or prevent the development of invasive cancer. Several key factors involved in colorectal cancer pathogenesis have already been identified including cyclooxygenase 2 (COX-2), nuclear factor kappa B (NF-κB), survivin and insulin-like growth factor-I (IGF-I). Clinical trials of COX-2 inhibitors have provided the “proof of principle” that inhibition of this enzyme can prevent the formation of colonic adenomas and potentially carcinomas, however concerns regarding the potential toxicity of these drugs have limited their use as a chemopreventative strategy. Curcumin, resveratrol and quercetin are chemopreventive agents that are able to suppress multiple signaling pathways involved in carcinogenesis and hence are attractive candidates for further research. Full article

(This article belongs to the Special Issue Pathogenesis and Prevention of Colorectal Cancer)

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Open AccessReview

Molecular Pathways Involved in Colorectal Cancer: Implications for Disease Behavior and Prevention

by Dora Colussi, Giovanni Brandi, Franco Bazzoli and Luigi Ricciardiello

Int. J. Mol. Sci. 2013, 14(8), 16365-16385; https://doi.org/10.3390/ijms140816365 - 07 Aug 2013

Cited by 343 | Viewed by 17213

Abstract

Research conducted during the past 30 years has increased our understanding of the mechanisms involved in colorectal cancer initiation and development. The findings have demonstrated the existence of at least three pathways: chromosomal instability, microsatellite instability and CpG island methylator phenotype. Importantly, new studies have shown that inflammation and microRNAs contribute to colorectal carcinogenesis. Recent data have demonstrated that several genetic and epigenetic changes are important in determining patient prognosis and survival. Furthermore, some of these mechanisms are related to patients’ response to drugs, such as aspirin, which could be used for both chemoprevention and treatment in specific settings. Thus, in the near future, we could be able to predict disease behavior based on molecular markers found on tumors, and direct the best treatment options for patients. Full article

(This article belongs to the Special Issue Pathogenesis and Prevention of Colorectal Cancer)

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Open AccessReview

Epigenetics Meets Radiation Biology as a New Approach in Cancer Treatment

by Joong-Gook Kim, Moon-Taek Park, Kyu Heo, Kwang-Mo Yang and Joo Mi Yi

Int. J. Mol. Sci. 2013, 14(7), 15059-15073; https://doi.org/10.3390/ijms140715059 - 18 Jul 2013

Cited by 39 | Viewed by 8582

Abstract

Cancer is a disease that results from both genetic and epigenetic changes. In recent decades, a number of people have investigated the disparities in gene expression resulting from variable DNA methylation alteration and chromatin structure modification in response to the environment. Especially, colon cancer is a great model system for investigating the epigenetic mechanism for aberrant gene expression alteration. Ionizing radiation (IR) could affect a variety of processes within exposed cells and, in particular, cause changes in gene expression, disruption of cell cycle arrest, and apoptotic cell death. Even though there is growing evidence on the importance of epigenetics and biological processes induced by radiation exposure in various cancer types including colon cancer, specific epigenetic alterations induced by radiation at the molecular level are incompletely defined. This review focuses on discussing possible IR-mediated changes of DNA methylation and histone modification in cancer. Full article

(This article belongs to the Special Issue Pathogenesis and Prevention of Colorectal Cancer)

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Open AccessReview

Colorectal Carcinogenesis: A Cellular Response to Sustained Risk Environment

by Kim Y. C. Fung, Cheng Cheng Ooi, Michelle H. Zucker, Trevor Lockett, Desmond B. Williams, Leah J. Cosgrove and David L. Topping

Int. J. Mol. Sci. 2013, 14(7), 13525-13541; https://doi.org/10.3390/ijms140713525 - 27 Jun 2013

Cited by 29 | Viewed by 7049

Abstract

The current models for colorectal cancer (CRC) are essentially linear in nature with a sequential progression from adenoma through to carcinoma. However, these views of CRC development do not explain the full body of published knowledge and tend to discount environmental influences. This paper proposes that CRC is a cellular response to prolonged exposure to cytotoxic agents (e.g., free ammonia) as key events within a sustained high-risk colonic luminal environment. This environment is low in substrate for the colonocytes (short chain fatty acids, SCFA) and consequently of higher pH with higher levels of free ammonia and decreased mucosal oxygen supply as a result of lower visceral blood flow. All of these lead to greater and prolonged exposure of the colonic epithelium to a cytotoxic agent with diminished aerobic energy availability. Normal colonocytes faced with this unfavourable environment can transform into CRC cells for survival through epigenetic reprogramming to express genes which increase mobility to allow migration and proliferation. Recent data with high protein diets confirm that genetic damage can be increased, consistent with greater CRC risk. However, this damage can be reversed by increasing SCFA supply by feeding fermentable fibre as resistant starch or arabinoxylan. High protein, low carbohydrate diets have been shown to alter the colonic environment with lower butyrate levels and apparently greater mucosal exposure to ammonia, consistent with our hypothesis. Evidence is drawn from in vivo and in vitro genomic and biochemical studies to frame experiments to test this proposition. Full article

(This article belongs to the Special Issue Pathogenesis and Prevention of Colorectal Cancer)

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