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Biomedical subjects

M M Bertagnolli

Publications and source records attributed to M M Bertagnolli.

At least 19 recordsLinked to original sources
PubMed2002

2-Methoxyestradiol induces p53-associated apoptosis of colorectal cancer cells.

Menopausal estrogen replacement therapy is thought to be responsible for the recent decline in colorectal cancer (CRC) incidence among women. In the C57BL/6J-Min/+ mouse, an animal model of CRC, 17beta-estradiol (E(2)) prevents tumor formation in ovariectomized females. We examined human CRC intestinal cell lines to determine whether particular E(2) metabolites produced anti-tumor effects. Treatment of CRC cells with 2-methoxyestradiol (2-MeOE(2)) increased expression of p53 and p21(WAF1/CIP1) proteins and induced apoptosis, but did not produce changes in expression of estrogen receptor (ER)alpha or ERbeta. The finding that 2-MeOE(2) induces p53-mediated colon cell apoptosis in vitro supports a role for 2-MeOE(2) as an endogenous mediator of intestinal tumor suppression.

2-Methoxyestradiol↗
PubMed2001

Progressive changes in adherens junction structure during intestinal adenoma formation in Apc mutant mice.

The C57BL/6J-Min/+ (Min/+) mouse bears a mutant Apc gene and therefore is an important in vivo model of intestinal tumorigenesis. Min/+ mice develop adenomas that exhibit loss of the wild-type Apc allele (Apc(Min/-)). Previously, we found that histologically normal enterocytes bearing a truncated Apc protein (Apc(Min/+)) migrated more slowly in vivo than enterocytes with either wild-type Apc (Apc(+/+)) or with heterozygous loss of Apc protein (Apc(1638N)). To study this phenotype further, we determined the effect of the Apc(Min) mutation upon cell-cell adhesion by examining the components of the adherens junction (AJ). We observed a reduced association between E-cadherin and beta-catenin in Apc(Min/+) enterocytes. Subcellular fractionation of proteins from Apc(+/+), Apc(Min/+), and Apc(Min/-) intestinal tissues revealed a cytoplasmic localization of intact E-cadherin only in Apc(Min/+), suggesting E-cadherin internalization in these enterocytes. beta-Catenin tyrosine phosphorylation was also increased in Apc(Min/+) enterocytes, consistent with its dissociation from E-cadherin. Furthermore, Apc(Min/+) enterocytes showed a decreased association between beta-catenin and receptor protein-tyrosine phosphatase beta/zeta (RPTPbeta/zeta), and Apc(Min/-) cells demonstrated an association between beta-catenin and receptor protein-tyrosine phosphatase gamma. In contrast to the Apc(Min/+) enterocytes, Apc(Min/-) adenomas displayed increased expression and association of E-cadherin, beta-catenin, and alpha-catenin relative to Apc(+/+) controls. These data show that Apc plays a role in regulating adherens junction structure and function in the intestine. In addition, discovery of these effects in initiated but histologically normal tissue (Apc(Min/+)) defines a pre-adenoma stage of tumorigenesis in the intestinal mucosa.

Adenoma↗
PubMed2001

Reciprocal expression of ERalpha and ERbeta is associated with estrogen-mediated modulation of intestinal tumorigenesis.

Menopausal hormone replacement therapy has been widely used to alleviate the symptoms of menopause and to decrease the detrimental effects of ovarian hormone loss on bone density and cardiovascular health. Multiple studies of colorectal cancer epidemiology also support a role for hormone replacement therapy in prevention of colorectal cancer. We studied the effect of ovariectomy and estrogen replacement on tumor formation in C57BL/6J-Min/+ (Min/+) mice, animals that bear a germline mutation in murine Apc. These mice develop multiple intestinal tumors that show loss of wild-type Apc protein. After ovariectomy, intestinal adenomas in Min/+ mice increased by 77% (P = 0.0004). Ovariectomized Min/+ mice that were treated with a replacement dose of 17beta-estradiol had the same number of tumors as Min/+ mice that were neither castrated nor treated with estrogen replacement (P = 0.85). Examination of estrogen receptor (ER) levels in intestinal tissue by immunoblot showed changes in relative expression levels of ERalpha and ERbeta, with highest ERalpha and lowest ERbeta expression in the normal-appearing intestine of Min/+ mice, and lowest ERalpha and highest ERbeta expression in the enterocytes of animals that received 17beta-estradiol. These results suggest that endogenous estrogens protect against Apc-associated tumor formation and that tumor prevention by 17beta-estradiol is associated with an increase in ERbeta and a decrease in ERalpha expression in the target tissue.

Adenomatous Polyposis Coli Protein↗
PubMed2001

(+)-Catechin inhibits intestinal tumor formation and suppresses focal adhesion kinase activation in the min/+ mouse.

Colorectal cancer is sensitive to dietary influences. Epidemiological data linking high intake of fruits and vegetables to decreased cancer risk have prompted the search for specific plant constituents implicated in tumor prevention. This task is difficult because of the complex chemical composition of plant foods and the multifactorial nature of carcinogenesis. Researchers are aided in this effort by the C57BL/6J-Min/+ (Min/+) mouse, an animal bearing a germline defect in Apc that is similar to the initiating genetic event in the majority of human colorectal cancers. In this study, we treated Min/+ mice with (+)-catechin, a phenolic antioxidant abundant in certain fruits. Administration of (+)-catechin in an AIN-76A diet at doses of 0.1 and 1% decreased the intestinal tumor number by 75 and 71%, respectively. Mechanistic studies linked this effect to (+)-catechin-induced changes in integrin-mediated intestinal cell-survival signaling, including structural alteration of the actin cytoskeleton and decreased focal adhesion kinase (FAK) tyrosine phosphorylation. Immunoblot analysis of small intestine scrapings from Min/+ mice and Apc+/+ wild-type C57BL/6J littermates together with excised Min/+ adenomas showed increased expression of phosphorylated FAK in the macroscopically normal enterocytes of untreated Min/+ mice and adenomas. Confirming the relevance of this signaling pathway, treatment of Min/+ mice with (+)-catechin reduced the expression of phosphorylated FAK to a level similar to the wild-type littermate controls. Thus, the natural abundance and favorable bioavailability of (+)-catechin make it a promising addition to the list of potential colorectal cancer chemopreventive agents.

3T3 Cells↗
PubMed2000

Inhibition of intestinal tumors by curcumin is associated with changes in the intestinal immune cell profile.

BACKGROUND: The C57BL/6J-Min/+ (Min/+) mouse bears a germline mutation in Apc and is therefore a model for familial adenomatous polyposis and sporadic colorectal cancer. Min/+ intestinal mucosa exhibits a marked tendency for spontaneous adenoma formation. Curcumin is a phenolic antioxidant known for its antitumor and immune modulatory functions in vitro. Curcumin prevents adenoma formation in Min/+ mice, through a mechanism that may be related to its immunomodulatory properties. MATERIALS AND METHODS: To study the relationship between intestinal immunity and curcumin-induced antitumor response, we used immunohistochemistry to characterize the effect of curcumin treatment on resident intestinal immune effector cells in Min/+ mice. RESULTS/CONCLUSION: These results show that mucosal CD4(+) T cells and B cells increase in animals treated with curcumin, suggesting that curcumin modulates lymphocyte-mediated immune functions.

Adenomatous Polyposis Coli Protein↗
PubMed2000

Combined sentinel lymphadenectomy and mohs micrographic surgery for high-risk cutaneous squamous cell carcinoma.

BACKGROUND: There are subgroups of cutaneous squamous cell carcinoma (SCC) that have a higher risk for both regional and distant metastasis. When cutaneous SCC does metastasize, it typically spreads first to local nodal groups. Sentinel lymph node (SLN) localization has been successfully used to evaluate nodal metastasis in breast carcinoma, melanoma, and other select tumors. It may also be useful in certain high-risk cutaneous SCCs. Currently, Mohs micrographic surgery is the treatment of choice for these tumors. METHODS: A patient presented with a high-risk recurrent SCC on the forehead. The regional nodal groups were clinically negative and radiographically negative by computed tomographic scan. Sentinel lymphadenectomy was performed by means of technetium 99m-radiolabeled sulfur colloid. The main tumor was resected with Mohs micrographic surgery. RESULTS: A left preauricular SLN was localized by lymphoscintigraphy. The SLN was located intraoperatively by means of a gamma probe and excised. Subsequent pathologic evaluation of the SLN was negative for evidence of metastatic SCC by light microscopy with hematoxylin and eosin, and with immunohistochemical stains for cytokeratins AE1 and AE3. The day after SLN excision, the tumor was removed via Mohs micrographic surgery with clear surgical margins after a total of 8 stages. Aggressive subclinical spread by both subcutaneous "skating" and perineural invasion was noted. CONCLUSION: The combination of Mohs micrographic surgery and sentinel lymphadenectomy is feasible and has theoretical utility in the management of a subset of cutaneous SCCs at high risk for metastasis. The ability of sentinel lymphadenectomy to identify regionally metastatic cutaneous SCC as well as the additive benefit of SLN and Mohs micrographic extirpation in the treatment of high-risk cutaneous SCC remain to be further clarified.

Aged↗
PubMed2000

Plant phenolics decrease intestinal tumors in an animal model of familial adenomatous polyposis.

Epidemiological studies consistently indicate that consumption of fruits and vegetables lowers cancer risk in humans and suggest that certain dietary constituents may be effective in preventing colon cancer. Plant-derived phenolic compounds manifest many beneficial effects and can potentially inhibit several stages of carcinogenesis in vivo. In this study, we investigated the efficacy of several plant-derived phenolics, including caffeic acid phenethyl ester (CAPE), curcumin, quercetin and rutin, for the prevention of tumors in C57BL/6J-Min/+ (Min/+) mice. These animals bear a germline mutation in the Apc gene and spontaneously develop numerous intestinal adenomas by 15 weeks of age. At a dietary level of 0.15%, CAPE decreased tumor formation in Min/+ mice by 63%. Curcumin induced a similar tumor inhibition. Quercetin and rutin, however, both failed to alter tumor formation at dietary levels of 2%. Examination of intestinal tissue from the treated animals showed that tumor prevention by CAPE and curcumin was associated with increased enterocyte apoptosis and proliferation. CAPE and curcumin also decreased expression of the oncoprotein beta-catenin in the enterocytes of the Min/+ mouse, an observation previously associated with an antitumor effect. These data place the plant phenolics CAPE and curcumin among a growing list of anti-inflammatory agents that suppress Apc-associated intestinal carcinogenesis.

Adenomatous Polyposis Coli↗
PubMed2000

Colon cancer chemopreventive drugs modulate integrin-mediated signaling pathways.

Epidemiological studies of colorectal cancer incidence suggest that the development of this disease can be modulated by dietary factors. Among the micronutrients showing significant efficacy in tumor prevention are polyphenolic antioxidants found in fruits and vegetables. Epidemiological studies also indicate that nonsteroidal anti-inflammatory drugs (NSAIDs) decrease the incidence of colorectal cancer. Integrin-mediated cell-matrix contact provides critical signaling that regulates cellular proliferation, migration, and apoptosis. A signaling mediator for this system is focal adhesion kinase (FAK). Thus far, FAK has not been identified as a target for the inhibitory action of any chemopreventive drug in vivo or in vitro. However, the loss of integrin-mediated cell-matrix contact can induce apoptosis (anoikis), and effective chemopreventive agents typically increase the rate of enterocyte apoptosis. Therefore, we asked whether the NSAID, sulindac sulfide, and the phenolic antioxidant, caffeic acid phenethyl ester (CAPE), affected FAK expression or tyrosine phosphorylation in human colon carcinoma cells. We show that subapoptotic doses of both sulindac sulfide and CAPE caused a rearrangement of the actin cytoskeleton and consequently the loss of focal adhesion plaques. These drugs also reduced the tyrosine phosphorylation of FAK and an associated factor, p130Cas. Steady-state levels of these proteins, together with other relevant signaling molecules, remained unchanged after treatments. Finally, we show that both CAPE and sulindac reduced cell invasion, a functional assay for the inhibition of signaling downstream of FAK. These data strongly suggest that chemopreventive drugs can regulate FAK activity. In conclusion, these novel studies add modulation of integrin-mediated signaling to the spectrum of activity of NSAIDs and plant phenolics.

Actins↗
PubMed1999

Genotype-phenotype correlation in murine Apc mutation: differences in enterocyte migration and response to sulindac.

The adenomatous polyposis coli (APC) gene product mediates coordinated cell growth in the intestinal mucosa. In humans, germ-line mutations of APC are associated with colorectal carcinogenesis, a process that varies in severity depending on the length of the protein resulting from the mutant allele. In a previous study of the C57BL/6J-Min/+ (Min/+) mouse, we found that the protein fragment resulting from truncation at codon 850 of murine Apc was associated with changes in enterocyte migration, proliferation, apoptosis, and beta-catenin expression. This effect was reversed upon treatment of Min/+ mice with the chemopreventive drug sulindac sulfide. In this study, we measured enterocyte migration in the Apc1638N mouse, an animal with an Apc mutation that yields no detectable APC protein. We found no difference in enterocyte migration, proliferation, apoptosis, or beta-catenin levels in the Apc1638N mouse when compared to wild-type littermates bearing two normal Apc alleles. Furthermore, administration of sulindac sulfide to Apc1638N mice did not alter enterocyte migration. These observations suggest that a dominant negative effect altering cell migration is exerted by the truncated APC protein present in the Min/+ mouse. These data also suggest that the effectiveness of chemopreventive agents in preventing Apc-related tumor formation may depend on which type of mutation is present.

Adenomatous Polyposis Coli↗
PubMed1999

Cyclooxygenase-2 as a target for prevention of colorectal cancer.

COX-2 is an isoenzyme of cyclooxygenase that is increased in response to growth factors, cytokines, and other mitogenic stimuli. Upregulation of COX-2 gene expression and functional activity is an early event in colorectal tumor formation. The long-term use of cyclooxygenase inhibitors, such as aspirin and nonsteroidal anti-inflammatory drugs, is associated with a decreased rate of colorectal tumors. This observation holds across a range of experimental models, from animal genetic tumor models to large epidemiologic studies of human sporadic colorectal cancer. Selective inhibitors of COX-2 were primarily developed to treat COX-2-related inflammation with minimal side effects. These drugs, however, may also provide safe, effective chemoprevention of colorectal neoplasia.

Animals↗
PubMed1999

Administration of an unconjugated bile acid increases duodenal tumors in a murine model of familial adenomatous polyposis.

Intestinal carcinogenesis involves the successive accumulation of multiple genetic defects until cellular transformation to an invasive phenotype occurs. This process is modulated by many epigenetic factors. Unconjugated bile acids are tumor promoters whose presence in intestinal tissues is regulated by dietary factors. We studied the role of the unconjugated bile acid, chenodeoxycholate, in an animal model of familial adenomatous polyposis. Mice susceptible to intestinal tumors as a result of a germline mutation in Apc (Min/+ mice) were given a 10 week dietary treatment with 0.5% chenodeoxycholate. Following this, the mice were examined to determine tumor number, enterocyte proliferation, apoptosis and beta-catenin expression. Intestinal tissue prostaglandin E2 (PGE2) levels were also assessed. Administration of chenodeoxycholate in the diet increased duodenal tumor number in Min/+ mice. Promotion of duodenal tumor formation was accompanied by increased beta-catenin expression in duodenal cells, as well as increased PGE2 in duodenal tissue. These data suggest that unconjugated bile acids contribute to periampullary tumor formation in the setting of an Apc mutation.

Adenomatous Polyposis Coli↗
PubMed1999

APC and intestinal carcinogenesis. Insights from animal models.

The APC protein is a crucial regulator of intestinal cell growth, and mutations in the APC gene are a common initial event in the process of human colorectal carcinogenesis. Animals bearing germline mutations in Apc are therefore important models for human colorectal cancer. These animals have been used both to understand the biology of human colorectal cancer and to screen for agents able to prevent malignant transformation of susceptible intestinal cells.

Adenomatous Polyposis Coli Protein↗
PubMed1998

The sulfide metabolite of sulindac prevents tumors and restores enterocyte apoptosis in a murine model of familial adenomatous polyposis.

Sulindac, a non-steroidal anti-inflammatory drug (NSAID), is effective in treating intestinal adenomas in humans with Familial Adenomatous Polyposis (FAP) and in preventing intestinal tumors in the C57Bl/6J-Min+ (Min) mouse, an animal model of FAP. Sulindac is a prodrug metabolized by the liver and intestinal flora to a sulfone, which has no anti-inflammatory activity, and a sulfide, which is the active anti-inflammatory metabolite. In this study, we determined which of these metabolites is responsible for the anti-tumor effect of sulindac in Min mice. Min mice were treated with either sulindac sulfone or sulindac sulfide (0.5 +/- 0.1 mg/day). Min mice and homozygous C57Bl/6J-(+/+) normal litter-mates lacking the Apc mutation (+/+) were used as controls. At 110 days of age, all mice were euthanized and their intestinal tracts examined. Control Min mice had 33.2 +/- 6.6 tumors per mouse compared to 0.6 +/- 0.3 tumors for sulindac sulfide-treated Min mice (P < 0.001) and 21.9 +/- 4.5 tumors per mouse for sulindac sulfone-treated Min mice (P > 0.05). Decreased enterocyte apoptosis was observed in Min control mice and Min mice treated with sulindac sulfone. Sulindac sulfide restored to normal the level of apoptosis in the mucosa of Min animals and decreased levels of PGE2 in the small intestine of treated Min animals by 59% (P < 0.001). These data suggest that the anti-tumor effect of sulindac in Apc-deficient animals is mediated by the sulfide metabolite and correlates with suppression of tissue prostaglandin synthesis.

Adenomatous Polyposis Coli↗
PubMed1998

Choledochal cysts in adults: a report of two cases and review of the literature.

A choledocal cyst is a dilation of some component of the biliary tract that may include both intra- and extra-hepatic sites. They are classified into six types, all of which are relatively rare. Previously, choledochal cysts were treated with biliary-enteric bypass procedures. The current recommendation is to attempt complete excision to minimize the known risk of malignancy and the development of recurrent cholangitis or pancreatitis that may occur in patients with these cystic lesions. Two cases are discussed in which type I choledochal cysts presented. One was removed from a 31-yr-old man who presented with vague abdominal complaints the other from a 32-yr-old man who presented with pancreatitis. The epidemiology, diagnosis, surgical treatment, and risk of cancer in choledochal cysts is described.

Adult↗
PubMed1998

Aspirin prevents tumors in a murine model of familial adenomatous polyposis.

BACKGROUND: Both human and murine studies suggest that anti-inflammatory drugs prevent intestinal neoplasia. The purpose of this study was to investigate the role of aspirin as a chemopreventive agent for colorectal cancer. METHODS: We administered aspirin to the Min/+ mouse, an animal with a germline mutation in Apc, a gene that is essential for normal epithelial cell growth and differentiation. Apc mutation increases cytoplasmic beta-catenin, a regulatory protein associated with the cytoskeleton. Min/+ mice develop multiple intestinal adenomas and exhibit altered cell growth in the preneoplastic intestinal epithelium. RESULTS: Aspirin decreased the rate of tumor formation in Min/+ mice by 44%. Aspirin also normalized enterocyte growth by increasing apoptosis and proliferation in the preneoplastic intestinal mucosa. Finally, aspirin produced a decrease in intracellular beta-catenin levels, suggesting that modulation of this protein is associated with tumor prevention. CONCLUSIONS: These data confirm a role for aspirin in suppression of Apc-associated intestinal carcinogenesis.

Adenomatous Polyposis Coli↗
PubMed1997

Apc gene mutation is associated with a dominant-negative effect upon intestinal cell migration.

Apc-associated intestinal tumor formation appears to require functional loss of both Apc alleles. Apc has, therefore, been classified as a tumor suppressor gene. Loss of APC protein function results in increased intracellular beta-catenin, a molecule important to both cell-cell adhesion and regulation of cellular growth. In mice bearing a germ-line Apc mutation, we found that enterocyte beta-catenin expression was also increased in histologically normal intestinal mucosa. Enterocyte crypt-villus migration was decreased by 25%, and treatment of Min/+ animals with sulindac sulfide normalized both beta-catenin expression and enterocyte migration. Our data suggest that alterations in enterocyte migration occur in cells bearing a single mutant Apc allele, and that sulindac sulfide may normalize enterocyte growth in these cells.

Analysis of Variance↗