Carcinogen-induced colon tumors in mice are chromosomally stable and are characterized by low-level microsatellite instability

Guda, Kishore; Upender, Madhvi B.; Belinsky, Glenn S.; Flynn, Christopher; Nakanishi, Masayoshi; Marino, Jillian; Ried, Thomas; Rosenberg, Daniel W.

doi:10.1038/sj.onc.1207489

Cited by 45 publications

(39 citation statements)

References 42 publications

(61 reference statements)

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“…Although these numerical differences suggested that gefitinib might inhibit the development of tumors with K-ras mutations, they did not reach statistical significance (P = 0.09). Moreover, this frequency of K-ras mutations was in agreement with prior reports (41). Because Ras was WT (and therefore regulated by EGFR) in ACF from gefitinibtreated animals, we infer that gefitinib would inhibit EGFR downstream effectors, such as ERK, an effector of Ras, in these ACF.…”

Section: Below)supporting

confidence: 92%

Epidermal Growth Factor Receptor Signaling Is Required for Microadenoma Formation in the Mouse Azoxymethane Model of Colonic Carcinogenesis

Fichera¹,

Little

Jagadeeswaran

et al. 2007

Cancer Research

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Colonic carcinogenesis involves the progressive dysregulation of homeostatic mechanisms that control growth. The epidermal growth factor (EGF) receptor (EGFR) regulates colonocyte growth and differentiation and is overexpressed in many human colon cancers. A requirement for EGFR in colonic premalignancy, however, has not been shown. In the current study, we used a specific EGFR antagonist, gefitinib, to investigate this role of the receptor in azoxymethane colonic premalignancy. The azoxymethane model shares many clinical, histologic, and molecular features of human colon cancer. Mice received azoxymethane i.p. (5 mg/kg/wk) or saline for 6 weeks. Animals were also gavaged with gefitinib (10 mg/kg body weight) or vehicle (DMSO) thrice weekly for 18 weeks, a dose schedule that inhibited normal receptor activation by exogenous EGF. Compared with control colonocytes [bromodeoxyuridine (BrdUrd), 2.2 F 1.2%], azoxymethane significantly increased proliferation (BrdUrd, 12.6 F 2.8%), whereas gefitinib inhibited this hyperproliferation (BrdUrd, 6.2 F 4.0%; <0.005). Azoxymethane significantly induced pro-transforming growth factor-A (6.4 F 1.3-fold) and increased phospho-(active) EGFR (5.9 F 1.1-fold), phospho-(active) ErbB2 (2.3 F 0.2-fold), and phospho-(active) extracellular signal-regulated kinase (3.3 F 0.4-fold) in premalignant colonocytes. Gefitinib inhibited activations of these kinases by >75% (P < 0.05). Gefitinib also significantly reduced the number of large aberrant crypt foci and decreased the incidence of colonic microadenomas from 75% to 33% (P < 0.05). Gefitinib concomitantly decreased cell cycle-regulating cyclin D1 and prostanoid biosynthetic enzyme cyclooxygenase-2 in microadenomas, suggesting that these regulators are key targets of EGFR in colonic carcinogenesis. These results show for the first time that EGFR signaling is required for early stages of colonic carcinogenesis. Our findings suggest, moreover, that inhibitors of EGFR might be useful in chemopreventive strategies in individuals at increased risk for colonic malignancies. [Cancer Res 2007;67(2):827-35]

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Section: Below)supporting

confidence: 92%

Epidermal Growth Factor Receptor Signaling Is Required for Microadenoma Formation in the Mouse Azoxymethane Model of Colonic Carcinogenesis

Fichera¹,

Little

Jagadeeswaran

et al. 2007

Cancer Research

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“…Azoxymethane induces large numbers of ACF and adenocarcinomas that are confined to the distal colon. In addition, because there is a gradual loss of Apc, the role of PGE 2 in h-catenin signaling can be evaluated during ACF formation (21,(30)(31)(32). Our results showed that loss of mPGES-1 significantly reduced ACF size, suggesting that promotion associated with PGE 2 can also occur early during tumorigenesis.…”

Section: Cancer Researchmentioning

confidence: 68%

“…PGE 2 has been shown to play a role in the indirect activation of hcatenin via inactivation of Axin and glycogen synthase kinase 3h (GSK-3h), proteins that form part of the h-catenin degradation complex (29). Unlike the complete loss of Apc function that occurs in Apc D14/+ -derived adenomas, the loss of Apc protein is a gradual process following azoxymethane treatment, accompanied by increased cytoplasmic and nuclear staining of h-catenin (21,(30)(31)(32).…”

Section: D14/+mentioning

confidence: 99%

Genetic Deletion of mPGES-1 Suppresses Intestinal Tumorigenesis

Nakanishi¹,

Montrose²,

et al. 2008

Self Cite

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Elevated levels of prostaglandin E 2 (PGE 2 ) are often found in colorectal cancers. Thus, nonsteroidal anti-inflammatory drugs, including selective cyclooxygenase-2 (COX-2) inhibitors, are among the most promising chemopreventive agents for colorectal cancer. However, their long-term use is restricted by the occurrence of adverse events believed to be associated with a global reduction in prostaglandin production. In the present study, we evaluated the chemopreventive efficacy of targeting the terminal synthase microsomal PGE 2 synthase 1 (mPGES-1), which is responsible for generating PGE 2 , in two murine models of intestinal cancer. We report for the first time that genetic deletion of mPGES-1 in Apc-mutant mice results in marked and persistent suppression of intestinal cancer growth by 66%, whereas suppression of large adenomas (>3 mm) was almost 95%. This effect occurred despite loss of Apc heterozygosity and B-catenin activation. However, we found that mPGES-1 deficiency was associated with a disorganized vascular pattern within primary adenomas as determined by CD31 immunostaining. We also examined the effect of mPGES-1 deletion on carcinogen-induced colon cancer. The absence of mPGES-1 reduced the size and number of preneoplastic aberrant crypt foci (ACF). Importantly, mPGES-1 deletion also blocked the nuclear accumulation of B-catenin in ACF, confirming that B-catenin is a critical target of PGE 2 procarcinogenic signaling in the colon. Our data show the feasibility of targeting mPGES-1 for cancer chemoprevention with the potential for improved tolerability over traditional nonsteroidal anti-inflammatory drugs and selective COX-2 inhibitors. [Cancer Res 2008;68(9):3251-9]

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“…We previously reported that the forcible transfection of mPGES-1 in combination with COX-2 into HEK293 cells led to cellular transformation with a concomitant and robust increase in PGE 2 (Kamei et al, 2003). It was also shown that overexpression of COX-2 induced genomic instability in MCF10A breast cancer cells (Singh et al, 2007) and that AOM-induced colon tumors in mice were chromosomally stable and were characterized by low-level microsatellite instability (Guda et al, 2004). mPGES-1-derived PGE 2 might enhance chemical carcinogen-initiated colon carcinogenesis by the induction of genomic instability.…”

Section: Discussionmentioning

confidence: 99%

Microsomal prostaglandin E synthase-1 is involved in multiple steps of colon carcinogenesis

et al. 2011

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Accumulating evidence indicates that cyclooxygenase (COX)-2-derived prostaglandin (PG) E 2 is involved in the development of various tumors, including colorectal cancer. However, the precise contribution of microsomal PGE synthase (mPGES)-1, a terminal enzyme that acts downstream of COX-2 in the PGE 2 -biosynthetic pathway, to multiple processes of tumor development is not yet fully understood. Here, we show the pro-tumorigenic role of mPGES-1 in chemical carcinogen-induced colon carcinogenesis and intrasplenic tumor transplantation models. Genetic deletion of mPGES-1 significantly reduced both the total number and size of colorectal polyps at 18 weeks after azoxymethane administration with reduced nuclear translocation of b-catenin, altered expression profiles of chemokines/cytokines and increased production of antitumorigenic PGs, prostaglandin D 2 and prostacyclin in tumor tissues. At an early stage (6 weeks), mPGES-1 deficiency significantly reduced the number of aberrant crypt foci, while its transgenic overexpression increased the number. Furthermore, the growth of intrasplenically transplanted tumor cells was suppressed in mPGES-1 knockout (KO) mice. Co-culture of tumor cells with bone marrow-derived macrophages (BM-MUs) isolated from wild-type (WT) mice resulted in the induction of mPGES-1 in BM-MUs and increased the growth of tumor cells in vitro, whereas mPGES-1-null BM-MUs failed to facilitate tumor growth. The adoptive transfer of WT BM-MUs into mPGES-1 KO mice restored the growth of transplanted tumor cells, indicating that mPGES-1 in MUs is important for the growth of adjacent tumor cells. Taken together, our findings suggest that the inhibition of mPGES-1 is an alternative therapeutic target for colorectal and possibly other cancers.

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Carcinogen-induced colon tumors in mice are chromosomally stable and are characterized by low-level microsatellite instability

Cited by 45 publications

References 42 publications

Epidermal Growth Factor Receptor Signaling Is Required for Microadenoma Formation in the Mouse Azoxymethane Model of Colonic Carcinogenesis

Epidermal Growth Factor Receptor Signaling Is Required for Microadenoma Formation in the Mouse Azoxymethane Model of Colonic Carcinogenesis

Genetic Deletion of mPGES-1 Suppresses Intestinal Tumorigenesis

Microsomal prostaglandin E synthase-1 is involved in multiple steps of colon carcinogenesis

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