Mouse model of colorectal and intestinal cancer

Last updated

Mouse models of colorectal cancer and intestinal cancer are experimental systems in which mice are genetically manipulated, fed a modified diet, or challenged with chemicals to develop malignancies in the gastrointestinal tract. These models enable researchers to study the onset, progression of the disease, and understand in depth the molecular events that contribute to the development and spread of colorectal cancer. They also provide a valuable biological system, to simulate human physiological conditions, suitable for testing therapeutics. [1] [2] [3]

Contents

Colorectal and intestinal cancer

Familial Adenomatous Polyposis

Familial Adenomatous Polyposis (FAP) is a hereditary disease that is characterized with development of numerous colon polyps. A genetic analysis of some FAP kindreds revealed that a common feature of the disease is a deletion of the APC gene . Further analysis of the APC gene revealed the existence of various mutations in cancer sufferers that also play a role in the onset of the sporadic form of colorectal cancer. [4]

APC mutant mice

The first mouse mutant in the Apc gene came from a colony of randomly mutagenized mice. [5] This mouse model is called Min (multiple intestinal neoplasia) mouse. It was found to carry a truncation mutation at codon 850 of the Apc gene. The Min mouse can develop up to 100 polyps in the small intestine in addition to colon tumors. Later, new knock-out mutants of the Apc gene were engineered. A truncating mutation at codon 716 (ApcΔ716) [6] results in a mouse that develops more than 300 polyps in the small intestine, while truncation at codon 1638 (Apc1638N) [7] results in the formation of about only 3 polyps in the same region of the gastrointestinal tract. [8] More recently a new mutant Apc mouse model was constructed in which multiple polyps form in the distal colon. [9] In this model mutation in the Cdx2 gene in the ApcΔ716 mouse model shifted the formation of the polyps from the intestine to the colon, resembling the human FAP. The Apc mutant mice are characterized by early lethality. There are genes modifying the cancer susceptibility of these mouse models. The most well-established is the modifier of Min locus (Mom1). [10] With combination of Min and Mom1 mutations the lifespan of FAP mouse models of colorectal cancer is increased. APC was found to associate with catenins. [11] Today we know that the beta-catenin protein (part of the Wnt signaling pathway) is implicated in colorectal carcinogenesis and its stability in the cell is regulated by APC. A mouse model with deregulation of beta-catenin levels was created. [12] The conditional stabilizing mutation in the beta-catenin gene caused formation of up to 3000 polyps in the small intestine of this mouse model. A mouse model carrying mutations in ApcΔ716 and Smad4 (mothers against decapentaplegic homolog 4) is characterized with development of invasive adenocarcinomas. [13]

Hereditary nonpolyposis colorectal cancer

The most frequent mutations in Hereditary nonpolyposis colorectal cancer (HNPCC) are mutations in the MSH2 and MLH1 genes. [14] These genes play an important role in repairing incorrectly positioned nucleotides. Another gene involved in DNA mismatch repair is Msh6. Both the Msh6 [15] and Msh2 [16] mutant mice develop gastrointestinal cancer but the tumours differ in their microsatellite instability (MI) status. While MSH2 deficiency promotes MI-high tumours, MSH6 deficiency results in MI-low tumours. Another component of the DNA repair machinery in the cell is the protein MLH1. Ablation of MLH1 in mice causes development of gastrointestinal tumours in the small intestine [17] – adenomas and invasive carcinomas. [18] The combination of MLH1 deficiency with the Apc1638N [6] mutant mouse results in strong reduction of viability and increased tumour burden. The tumours were classified as adenomas, invasive adenocarcinomas and late stage carcinomas. Similarly, mice deficient for Msh2 combined with Apc Min demonstrate accelerated rate of tumorigenesis. [19] Another similar mouse model of HNPCC is the combination of PMS2 mutant mouse with the Min Apc allele resulting in increased number of tumours in the gastrointestinal tract compared to Min. [20] Yet these adenocarcinomas do not metastasize and their histopathology is similar to that of the right side colon cancer in human with frequent mutation of the type II receptor for TGF-β.

Mutations in other genes

Mice with mutations in transforming growth factor-β1 gene introduced into 129/Sv Rag2 mutant mouse [21] accelerates adenocarcinomas with strong local invasion suggesting a role for genetic background in tumor development. Colon-specific expression of activated mutant of K-ras (protein) (K-rasG12D) results in development of single or multiple lesions. [22] Oncogenic K-rasG12D allele activated in colon epithelium induces expression of procarcinogenic protein kinase C-βII (PKCβII) and increases cell proliferation of epithelial cells, while in the distal colon the mutant form of K-ras has the opposite effects on PKCβII expression and cell proliferation. [23] Treatment of this mouse model with the procarcinogen azoxymethane (AOM) leads to formation of dysplastic microadenomas in the proximal but not in the distal colon. Thus the K-rasG12D mutant is a valuable mouse model of proximal colon carcinogenesis. Mutation in the Muc2 gene causes adenomas and adenocarcinomas in the intestine of mice. [24]

Human inflammatory bowel disease is a group of inflammatory conditions in the large and small intestine. It is well known that chronic inflammation in the colon can lead to cancer. There are genetic mouse models for inflammatory bowel disease associated colon cancer. Interleukin 10 knock out mice develop invasive adenocarcinoma in the colon. [25] Mutant mice for interleukin 2 and beta microglobulin genes also produce ulcerative colitis-like phenotype and develop adenocarcinomas in the colon. [26] A mouse mutant for N-cadherin suffers inflammatory bowel disease conditions and adenomas but does not develop carcinomas. [27]

Humans with high levels of the diet-related bile acid deoxycholate (DOC) in their colons are at a substantially increased risk of developing colon cancer (see Bile acids and colon cancer). A diet-related mouse model of colon cancer was devised. [28] [29] In this model, wild type mice are fed a standard diet plus DOC to give a level of DOC in mouse colon comparable to that in the colons of humans on a high fat diet. [28] After 8–10 months, 45% to 56% of the mice developed colonic adenocarcinomas, and no mice had cancers of the small intestine.

On the basis of histopathology and by expression of specific markers, the colonic tumors in the mice were virtually identical to those in humans. [29] In humans, characteristic aberrant changes in molecular markers are detected both in field defects surrounding cancers (from which the cancers arise) and within cancers. In the colonic tissues of mice fed diet plus DOC similar changes in biomarkers occurred. Thus, 8-OH-dG was increased, DNA repair protein ERCC1 was decreased, autophagy protein beclin-1 was increased and, in the stem cell region at the base of crypts, there was substantial nuclear localization of beta-catenin as well as increased cytoplasmic beta-catenin. However, in mice fed diet plus DOC plus the antioxidant chlorogenic acid, the frequency of colon cancer was reduced. [28] Furthermore, when evaluated for ERCC1, beclin-1, and beta-catenin in the stem cell region of crypts, the colonic tissues of chlorogenic acid-fed mice showed amelioration of the molecular aberrancies, [29] suggesting that chlorogenic acid is protective at the molecular level against colon cancer. This is the first diet-related model of colon cancer that closely parallels human progression to colon cancer, both at the histopathology level as well as in its molecular profile.

Chemically-induced colorectal cancer

Azoxymethane (AOM) is a genotoxic colonic carcinogen and is routinely used to induce colon tumours in mice. [30] The AOM-induced tumours form in the last three centimeters of the distal colon but a p21 knock out mouse treated with AOM shows tumour distribution throughout the colon. [31] AOM-induced tumours are characterized with mutations in the Apc gene. [32]

A novel inflammation-related mouse model of colorectal carcinogenesis combines AOM and dextran sodium sulphate (DSS) to induce colon lesions, positive for beta-catenin, COX-2 and inducible nitric oxide synthase. [33]

See also

Related Research Articles

<span class="mw-page-title-main">Colorectal cancer</span> Cancer of the colon or rectum

Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the colon or rectum. Signs and symptoms may include blood in the stool, a change in bowel movements, weight loss, and fatigue. Most colorectal cancers are due to old age and lifestyle factors, with only a small number of cases due to underlying genetic disorders. Risk factors include diet, obesity, smoking, and lack of physical activity. Dietary factors that increase the risk include red meat, processed meat, and alcohol. Another risk factor is inflammatory bowel disease, which includes Crohn's disease and ulcerative colitis. Some of the inherited genetic disorders that can cause colorectal cancer include familial adenomatous polyposis and hereditary non-polyposis colon cancer; however, these represent less than 5% of cases. It typically starts as a benign tumor, often in the form of a polyp, which over time becomes cancerous.

<span class="mw-page-title-main">Gardner's syndrome</span> Medical condition

Gardner's syndrome is a subtype of familial adenomatous polyposis (FAP). Gardner syndrome is an autosomal dominant form of polyposis characterized by the presence of multiple polyps in the colon together with tumors outside the colon. The extracolonic tumors may include osteomas of the skull, thyroid cancer, epidermoid cysts, fibromas, as well as the occurrence of desmoid tumors in approximately 15% of affected individuals.

<span class="mw-page-title-main">Familial adenomatous polyposis</span> Medical condition

Familial adenomatous polyposis (FAP) is an autosomal dominant inherited condition in which numerous adenomatous polyps form mainly in the epithelium of the large intestine. While these polyps start out benign, malignant transformation into colon cancer occurs when they are left untreated. Three variants are known to exist, FAP and attenuated FAP are caused by APC gene defects on chromosome 5 while autosomal recessive FAP is caused by defects in the MUTYH gene on chromosome 1. Of the three, FAP itself is the most severe and most common; although for all three, the resulting colonic polyps and cancers are initially confined to the colon wall. Detection and removal before metastasis outside the colon can greatly reduce and in many cases eliminate the spread of cancer.

<span class="mw-page-title-main">Hereditary nonpolyposis colorectal cancer</span> Autosomal dominant genetic condition associated with a high risk of cancer eg in the colon

Hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome is an autosomal dominant genetic condition that is associated with a high risk of colon cancer as well as other cancers including endometrial cancer, ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. The increased risk for these cancers is due to inherited genetic mutations that impair DNA mismatch repair. It is a type of cancer syndrome. Because patients with Lynch syndrome can have polyps, the term HNPCC has fallen out of favor.

<span class="mw-page-title-main">Neoplasm</span> Abnormal mass of tissue as a result of abnormal growth or division of cells

A neoplasm is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists in growing abnormally, even if the original trigger is removed. This abnormal growth usually forms a mass, when it may be called a tumour or tumor.

<span class="mw-page-title-main">Mismatch repair cancer syndrome</span> Medical condition

Mismatch repair cancer syndrome (MMRCS) is a cancer syndrome associated with biallelic DNA mismatch repair mutations. It is also known as Turcot syndrome and by several other names.

Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abnormal cell division. Cell division is a physiological process that occurs in almost all tissues and under a variety of circumstances. Normally, the balance between proliferation and programmed cell death, in the form of apoptosis, is maintained to ensure the integrity of tissues and organs. According to the prevailing accepted theory of carcinogenesis, the somatic mutation theory, mutations in DNA and epimutations that lead to cancer disrupt these orderly processes by interfering with the programming regulating the processes, upsetting the normal balance between proliferation and cell death. This results in uncontrolled cell division and the evolution of those cells by natural selection in the body. Only certain mutations lead to cancer whereas the majority of mutations do not.

<span class="mw-page-title-main">DNA mismatch repair</span> System for fixing base errors of DNA replication

DNA mismatch repair (MMR) is a system for recognizing and repairing erroneous insertion, deletion, and mis-incorporation of bases that can arise during DNA replication and recombination, as well as repairing some forms of DNA damage.

<span class="mw-page-title-main">Adenomatous polyposis coli</span> Protein-coding gene in the species Homo sapiens

Adenomatous polyposis coli (APC) also known as deleted in polyposis 2.5 (DP2.5) is a protein that in humans is encoded by the APC gene. The APC protein is a negative regulator that controls beta-catenin concentrations and interacts with E-cadherin, which are involved in cell adhesion. Mutations in the APC gene may result in colorectal cancer and desmoid tumors.

<span class="mw-page-title-main">Fundic gland polyposis</span> Medical condition

Fundic gland polyposis is a medical syndrome where the fundus and the body of the stomach develop many fundic gland polyps. The condition has been described both in patients with familial adenomatous polyposis (FAP) and attenuated variants (AFAP), and in patients in whom it occurs sporadically.

<span class="mw-page-title-main">Microsatellite instability</span> Condition of genetic hypermutability

Microsatellite instability (MSI) is the condition of genetic hypermutability that results from impaired DNA mismatch repair (MMR). The presence of MSI represents phenotypic evidence that MMR is not functioning normally.

<span class="mw-page-title-main">Muir–Torre syndrome</span> Medical condition

Muir–Torre syndrome is a rare hereditary, autosomal dominant cancer syndrome that is thought to be a subtype of HNPCC. Individuals are prone to develop cancers of the colon, genitourinary tract, and skin lesions, such as keratoacanthomas and sebaceous tumors. The genes affected are MLH1, MSH2, and more recently, MSH6, and are involved in DNA mismatch repair.

<span class="mw-page-title-main">MSH2</span> Protein-coding gene in the species Homo sapiens

DNA mismatch repair protein Msh2 also known as MutS homolog 2 or MSH2 is a protein that in humans is encoded by the MSH2 gene, which is located on chromosome 2. MSH2 is a tumor suppressor gene and more specifically a caretaker gene that codes for a DNA mismatch repair (MMR) protein, MSH2, which forms a heterodimer with MSH6 to make the human MutSα mismatch repair complex. It also dimerizes with MSH3 to form the MutSβ DNA repair complex. MSH2 is involved in many different forms of DNA repair, including transcription-coupled repair, homologous recombination, and base excision repair.

<span class="mw-page-title-main">MLH1</span> Protein-coding gene in the species Homo sapiens

DNA mismatch repair protein Mlh1 or MutL protein homolog 1 is a protein that in humans is encoded by the MLH1 gene located on chromosome 3. It is a gene commonly associated with hereditary nonpolyposis colorectal cancer. Orthologs of human MLH1 have also been studied in other organisms including mouse and the budding yeast Saccharomyces cerevisiae.

<span class="mw-page-title-main">Colorectal polyp</span> Growth found in bowel wall

A colorectal polyp is a polyp occurring on the lining of the colon or rectum. Untreated colorectal polyps can develop into colorectal cancer.

<span class="mw-page-title-main">O-6-methylguanine-DNA methyltransferase</span> Mammalian protein found in Homo sapiens

O6-alkylguanine DNA alkyltransferase (also known as AGT, MGMT or AGAT) is a protein that in humans is encoded by the O6-methylguanine DNA methyltransferase (MGMT) gene. O6-methylguanine DNA methyltransferase is crucial for genome stability. It repairs the naturally occurring mutagenic DNA lesion O6-methylguanine back to guanine and prevents mismatch and errors during DNA replication and transcription. Accordingly, loss of MGMT increases the carcinogenic risk in mice after exposure to alkylating agents. The two bacterial isozymes are Ada and Ogt.

<span class="mw-page-title-main">AXIN2</span> Protein-coding gene in the species Homo sapiens

Axin-2 also known as axin-like protein (Axil) or axis inhibition protein 2 (AXIN2) or conductin is a protein that in humans is encoded by the AXIN2 gene.

Somatic evolution is the accumulation of mutations and epimutations in somatic cells during a lifetime, and the effects of those mutations and epimutations on the fitness of those cells. This evolutionary process has first been shown by the studies of Bert Vogelstein in colon cancer. Somatic evolution is important in the process of aging as well as the development of some diseases, including cancer.

<span class="mw-page-title-main">Histopathology of colorectal adenocarcinoma</span>

The histopathology of colorectal cancer of the adenocarcinoma type involves analysis of tissue taken from a biopsy or surgery. A pathology report contains a description of the microscopical characteristics of the tumor tissue, including both tumor cells and how the tumor invades into healthy tissues and finally if the tumor appears to be completely removed. The most common form of colon cancer is adenocarcinoma, constituting between 95% and 98% of all cases of colorectal cancer. Other, rarer types include lymphoma, adenosquamous and squamous cell carcinoma. Some subtypes have been found to be more aggressive.

hPG80 refers to the extracellular and oncogenic version of progastrin. This name first appeared in a scientific publication in January 2020. Until that date, scientific publications only mention 'progastrin', without necessarily explicitly specifying whether it is intracellular or extracellular in the tumor pathological setting.

References

  1. ↑ Golovko, D; Kedrin, D; Yilmaz, ÖH; Roper, J (2015). "Colorectal cancer models for novel drug discovery". Expert Opinion on Drug Discovery. 10 (11): 1217–29. doi:10.1517/17460441.2015.1079618. PMC   4872297 . PMID   26295972.
  2. ↑ Oh, BY; Hong, HK; Lee, WY; Cho, YB (28 February 2017). "Animal models of colorectal cancer with liver metastasis". Cancer Letters. 387: 114–120. doi:10.1016/j.canlet.2016.01.048. PMID   26850374.
  3. ↑ Evans, JP; Sutton, PA; Winiarski, BK; Fenwick, SW; Malik, HZ; Vimalachandran, D; Tweedle, EM; Costello, E; Palmer, DH; Park, BK; Kitteringham, NR (February 2016). "From mice to men: Murine models of colorectal cancer for use in translational research". Critical Reviews in Oncology/Hematology. 98: 94–105. doi:10.1016/j.critrevonc.2015.10.009. PMID   26558688.
  4. ↑ Groden J, Thliveris A, Samowitz W, et al. (1991). "Identification and characterization of the familial adenomatous polyposis coli gene". Cell . 66 (3): 589–600. doi:10.1016/0092-8674(81)90021-0. PMID   1651174. S2CID   38325198.
  5. ↑ Moser AR, Pitot HC, Dove WF (1990). "A dominant mutation that predisposes to multiple intestinal neoplasia in the mouse". Science . 247 (4940): 322–4. doi:10.1126/science.2296722. PMID   2296722.
  6. 1 2 Fodde R, Edelmann W, Yang K, et al. (1994). "A targeted chain-termination mutation in the mouse Apc gene results in multiple intestinal tumors". Proc. Natl. Acad. Sci. U.S.A. 91 (19): 8969–73. Bibcode:1994PNAS...91.8969F. doi: 10.1073/pnas.91.19.8969 . PMC   44728 . PMID   8090754.
  7. ↑ Oshima M, Oshima H, Kitagawa K, Kobayashi M, Itakura C, Taketo M (1995). "Loss of Apc heterozygosity and abnormal tissue building in nascent intestinal polyps in mice carrying a truncated Apc gene". Proc. Natl. Acad. Sci. U.S.A. 92 (10): 4482–6. Bibcode:1995PNAS...92.4482O. doi: 10.1073/pnas.92.10.4482 . PMC   41968 . PMID   7753829.
  8. ↑ Taketo MM (2006). "Mouse models of gastrointestinal tumors". Cancer Sci. 97 (5): 355–61. doi: 10.1111/j.1349-7006.2006.00190.x . PMID   16630131.
  9. ↑ Aoki K, Tamai Y, Horiike S, Oshima M, Taketo MM (2003). "Colonic polyposis caused by mTOR-mediated chromosomal instability in Apc+/Delta716 Cdx2+/- compound mutant mice". Nat. Genet. 35 (4): 323–30. doi:10.1038/ng1265. hdl: 2433/147469 . PMID   14625550. S2CID   22623315.
  10. ↑ Dietrich WF, Lander ES, Smith JS, et al. (1993). "Genetic identification of Mom-1, a major modifier locus affecting Min-induced intestinal neoplasia in the mouse". Cell . 75 (4): 631–9. doi:10.1016/0092-8674(93)90484-8. PMID   8242739.
  11. ↑ Su LK, Vogelstein B, Kinzler KW (1993). "Association of the APC tumor suppressor protein with catenins". Science . 262 (5140): 1734–7. Bibcode:1993Sci...262.1734S. doi:10.1126/science.8259519. PMID   8259519.
  12. ↑ Harada N, Tamai Y, Ishikawa T, et al. (1999). "Intestinal polyposis in mice with a dominant stable mutation of the beta-catenin gene". EMBO J. 18 (21): 5931–42. doi:10.1093/emboj/18.21.5931. PMC   1171659 . PMID   10545105.
  13. ↑ Takaku K, Oshima M, Miyoshi H, Matsui M, Seldin MF, Taketo MM (1998). "Intestinal tumorigenesis in compound mutant mice of both Dpc4 (Smad4) and Apc genes". Cell . 92 (5): 645–56. doi: 10.1016/S0092-8674(00)81132-0 . PMID   9506519.
  14. ↑ Kolodner R (1996). "Biochemistry and genetics of eukaryotic mismatch repair". Genes Dev. 10 (12): 1433–42. doi: 10.1101/gad.10.12.1433 . PMID   8666228.
  15. ↑ Edelmann W, Yang K, Umar A, et al. (1997). "Mutation in the mismatch repair gene Msh6 causes cancer susceptibility". Cell . 91 (4): 467–77. doi: 10.1016/S0092-8674(00)80433-X . PMID   9390556.
  16. ↑ Reitmair AH, Redston M, Cai JC, et al. (1996). "Spontaneous intestinal carcinomas and skin neoplasms in Msh2-deficient mice". Cancer Res. 56 (16): 3842–9. PMID   8706033.
  17. ↑ Baker SM, Plug AW, Prolla TA, et al. (1996). "Involvement of mouse Mlh1 in DNA mismatch repair and meiotic crossing over". Nat. Genet. 13 (3): 336–42. doi:10.1038/ng0796-336. PMID   8673133. S2CID   37096830.
  18. ↑ Edelmann W, Yang K, Kuraguchi M, et al. (1999). "Tumorigenesis in Mlh1 and Mlh1/Apc1638N mutant mice". Cancer Res. 59 (6): 1301–7. PMID   10096563.
  19. ↑ Reitmair AH, Cai JC, Bjerknes M, et al. (1996). "MSH2 deficiency contributes to accelerated APC-mediated intestinal tumorigenesis". Cancer Res. 56 (13): 2922–6. PMID   8674041.
  20. ↑ Baker SM, Harris AC, Tsao JL, et al. (1998). "Enhanced intestinal adenomatous polyp formation in Pms2-/-;Min mice". Cancer Res. 58 (6): 1087–9. PMID   9515784.
  21. ↑ Engle SJ, Hoying JB, Boivin GP, Ormsby I, Gartside PS, Doetschman T (1999). "Transforming growth factor beta1 suppresses nonmetastatic colon cancer at an early stage of tumorigenesis". Cancer Res. 59 (14): 3379–86. PMID   10416598.
  22. ↑ Janssen KP, el-Marjou F, Pinto D, et al. (2002). "Targeted expression of oncogenic K- ras in intestinal epithelium causes spontaneous tumorigenesis in mice". Gastroenterology . 123 (2): 492–504. doi: 10.1053/gast.2002.34786 . PMID   12145803.
  23. ↑ Calcagno SR, Li S, Colon M, et al. (2008). "Oncogenic K-ras promotes early carcinogenesis in the mouse proximal colon". Int. J. Cancer . 122 (11): 2462–70. doi:10.1002/ijc.23383. PMC   3908548 . PMID   18271008.
  24. ↑ Velcich A, Yang W, Heyer J, et al. (2002). "Colorectal cancer in mice genetically deficient in the mucin Muc2". Science . 295 (5560): 1726–9. Bibcode:2002Sci...295.1726V. doi:10.1126/science.1069094. PMID   11872843. S2CID   19425315.
  25. ↑ Berg DJ, Davidson N, Kühn R, et al. (1996). "Enterocolitis and colon cancer in interleukin-10-deficient mice are associated with aberrant cytokine production and CD4(+) TH1-like responses". J. Clin. Invest. 98 (4): 1010–20. doi:10.1172/JCI118861. PMC   507517 . PMID   8770874.
  26. ↑ Shah SA, Simpson SJ, Brown LF, et al. (1998). "Development of colonic adenocarcinomas in a mouse model of ulcerative colitis". Inflamm. Bowel Dis. 4 (3): 196–202. doi: 10.1002/ibd.3780040305 . PMID   9741021. S2CID   39002611.
  27. ↑ Hermiston ML, Gordon JI (1995). "Inflammatory bowel disease and adenomas in mice expressing a dominant negative N-cadherin". Science . 270 (5239): 1203–7. Bibcode:1995Sci...270.1203H. doi:10.1126/science.270.5239.1203. PMID   7502046. S2CID   19696029.
  28. 1 2 3 Bernstein C, Holubec H, Bhattacharyya AK, Nguyen H, Payne CM, Zaitlin B, Bernstein H (2011). "Carcinogenicity of deoxycholate, a secondary bile acid". Arch. Toxicol. 85 (8): 863–71. doi:10.1007/s00204-011-0648-7. PMC   3149672 . PMID   21267546.
  29. 1 2 3 Prasad AR, Prasad S, Nguyen H, Facista A, Lewis C, Zaitlin B, Bernstein H, Bernstein C (2014). "Novel diet-related mouse model of colon cancer parallels human colon cancer". World J Gastrointest Oncol. 6 (7): 225–43. doi:10.4251/wjgo.v6.i7.225. PMC   4092339 . PMID   25024814.
  30. ↑ Neufert C, Becker C, Neurath MF (2007). "An inducible mouse model of colon carcinogenesis for the analysis of sporadic and inflammation-driven tumor progression". Nat Protoc . 2 (8): 1998–2004. doi:10.1038/nprot.2007.279. PMID   17703211. S2CID   28778351.
  31. ↑ Poole AJ, Heap D, Carroll RE, Tyner AL (2004). "Tumor suppressor functions for the Cdk inhibitor p21 in the mouse colon". Oncogene . 23 (49): 8128–34. doi: 10.1038/sj.onc.1207994 . PMID   15377995.
  32. ↑ Maltzman T, Whittington J, Driggers L, Stephens J, Ahnen D (1997). "AOM-induced mouse colon tumors do not express full-length APC protein". Carcinogenesis . 18 (12): 2435–9. doi: 10.1093/carcin/18.12.2435 . PMID   9450492.
  33. ↑ Tanaka T, Kohno H, Suzuki R, Yamada Y, Sugie S, Mori H (2003). "A novel inflammation-related mouse colon carcinogenesis model induced by azoxymethane and dextran sodium sulfate". Cancer Sci. 94 (11): 965–73. doi:10.1111/j.1349-7006.2003.tb01386.x. PMID   14611673. S2CID   6538164.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.