Regression Of Adenomas Research Articles

Cis-vaccinic acid, Dibutyl-Cyanamide and 9, 12-Octadecadienoic acid from pistachio (Pistachia vera) seed coat (PSCE) induced nuclear damage and cytotoxicity in human colon cancer HT-115 cells

Current strategy for colorectal cancer (CRC) therapy like regular intake of non-steroidal anti-inflammatory drugs (NSAIDs) may reduce the risk of developing CRC but they induce the regression of adenomas. Even the CRC management technique include colectomy, have not yet been proven to reduce mortality. The present study aimed to reduce the susceptibility of CRC via controlling cellular oxidative stress, inflammation and caspase depended apoptosis in HT-115 human colorectal cancer cells using pistachio seed coat extract as nutritional therapy. Increasing concentrations of pistachio seed coat ethyl acetate extract (PSCE) were applied to HT-115 cells, which were incubated for 24 h and 48 h. The IC50 values were 14 mg/dl after 24 h, and and 7.5 mg/dl after 48 h. Acridine orange/ ethidium bromide staining confirmed the presence of 32% early apoptotic, 27% pre-apoptotic, 12% apoptotic, and 6% necrotic cells after 48 h. PSCE at 14 mg/dl significantly increased the antioxidant capacity via the expression of CYP1A and GSK3β, and decreased inflammatory agents via decreasing NF-κb, TNF-α, COX-2 and PGE-2 expression three-fold after 48 h. The expression of the tumor suppression related genes p53 and mdm2, and the apoptosis related genes Bax, Bcl-2, Caspase 3, p21, and PCNA levels increased one-fold, and levels of mdm2, Bcl-2 and PCNA decreased after PME treatment of 48 h. PSCE effectively controlled colon cancer cell proliferation via the caspase-dependent mitochondrial mediated apoptotic pathway.
 Keywords: Pistachia vera, cytotoxicity, human colon cancer, Cis-Vaccininc acid, apoptosis

68. Hemorrhagic shock due to ruptured hepatic adenoma secondary to oral norethindrone acetate in a patient with type 3 von Willebrand disease: a case report

<h3>Background</h3> Patients with von Willebrand's disease (vWD) often require menstrual suppression in order to avoid episodes of heavy bleeding. While multiple hormone-based options are appropriate for these patients, specific side effects and clinical considerations based on the type and severity of vWD need further study. We discuss refinement of treatment options for menorrhagia for an adolescent with type 3 vWD who presented with a complication likely related to chronic progestin exposure. <h3>Case</h3> Patient C.D. was diagnosed with type 3 vWD in infancy and presented at 11 years-old for management of menorrhagia with a goal of amenorrhea. She was initially started on oral norethindrone acetate alone 3 times daily, which was continued for years to control breakthrough bleeding while receiving injectable progestins followed by the etonorgestrel-releasing implant. At 15 years-old, C.D. presented to the emergency room after 1 day of severe abdominal pain. She was found to be hypotensive with peritoneal signs on exam. CT demonstrated multiple hepatic masses, the largest being 9 cm with active contrast extravasation suggesting a bleeding adenoma with associated hemoperitoneum. She underwent an emergent right hepatic lobe embolization by interventional radiology. She recovered in the pediatric ICU with stabilization of her bleeding. The etiology of her hepatic adenomas was suspected to be chronic progestin use. After department discussions with hematology and gynecology, the oral norethindrone acetate was discontinued during her hospital course and she experienced withdrawal bleeding. On hospital day 13, the patient's contraceptive implant was removed and a levonorgestrel-releasing IUD was placed, which expelled 2 days later in the setting of heavy vaginal bleeding. C.D. received depot-medroxyprogesterone and was discharged home on daily recombinant VWF. At 1-month follow-up, the patient was amenorrheic and had stable hepatic masses on repeat imaging. The patient was maintained on injectable progestins with plans to trial a progestin IUD in the future. <h3>Comments</h3> Hepatic adenoma is a known complication of estrogen-containing medications and a rare side effect from peripheral conversion of oral progestins. A few case reports have shown regression of hepatic adenomas after cessation of progestin therapy. Furthermore, menses suppression for patients with severe vWD is critical to avoid menorrhagia. Patients with type 3 vWD particularly have limited pharmacologic options for preventing heavy menses. Through this case report, we discuss the management options for menstrual suppression and control of menorrhagia in patients with severe vWD with consideration of potential morbid side effects, and explore areas of further research of treatment regimens.

Abstract LB-094: Systemic RSPO1 delivery leads to regression of intestinal adenomas via activation of the TGFβ/SMAD pathway

Abstract Colorectal cancers (CRCs) most commonly develop from adenomas harboring a mutant APC gene that leads to aberrant activation of the canonical Wnt/ß-catenin pathway. One of the mechanisms of adenoma progression involves the PROX1 transcription factor that promotes tumor dysplasia and progression in CRC. In the normal intestinal epithelial cells, ligands of the R-Spondin (RSPO) family are able to enhance the canonical Wnt pathway activity by binding to receptor proteins of the LGR family, such as LGR5. Tumorigenic RSPO gene fusions have recently been discovered in CRCs, but the role of RSPOs in cancer is incompletely known. We previously reported that TGFß induced apoptosis of APC-mutant organoids, including the LGR5+ stem cells, was mediated by the proapoptotic protein BIM, whereas wild-type intestinal crypts were markedly less sensitive to TGFß. The KRAS oncogene increased apoptosis resistance in the adenomas via activation of the Erk1/2 kinase pathway, which led to Bim down-regulation and increased resistance to TGFß. A subsequent study showed that RSPO/LGR5 can inhibit the in vitro growth of cultured human CRC cell line by activating the TGFß/SMAD signaling pathway. Because we were interested in analyzing the effect of exogenous Wnt signals on PROX1 expression in intestinal tumorigenesis, we constructed AAV-vectors for systemic expression of a soluble RSPO1 protein in ApcMin/+ mice. We found that the RSPO1-Fc fusion protein suppresses the Wnt/ß-catenin signaling activity in intestinal adenomas and in adenoma-derived intestinal organoids ex vivo, but not in normal intestinal epithelial cells. In the Apc mutant cells, the RSPO1-Fc fusion protein activated the TGFß/SMAD signaling pathway to suppress several Wnt target genes and adenoma growth, which effect was rescued suppressed by the TGFß receptor kinase inhibitor SB-431542. Simultaneously, RSPO1-Fc induced proliferation of the normal intestinal stem cells, giving them a growth advantage over the mutant cells, which enabled the intestinal epithelium to eventually outgrow the adenoma cells. Prolonged systemic expression of AAV-RSPO1-Fc decreased significantly the number of the intestinal adenomas and improved the overall survival of ApcMin/+ mice. Thus RSPO1-Fc provides the normal intestinal epithelial cells a growth advantage when compared to the adenoma cells, which eventually leads to the extrusion of the adenomatous tissue. An attractive idea now is to exploit such differential response of normal vs. cancer cells in cancer therapy. Citation Format: Marianne Lähde, Sarika Heino, Jenny Högström, Veli-Matti Leppänen, Seppo Kaijalainen, Olli Ritvos, Owen Sansom, Kari Alitalo. Systemic RSPO1 delivery leads to regression of intestinal adenomas via activation of the TGFβ/SMAD pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-094.

Cabergoline Withdrawal Before and After Menopause: Outcomes in Microprolactinomas

Natural course of prolactinomas after menopause is not fully elucidated. The aim of this study was to compare recurrence rate after cabergoline withdrawal in premenopausal vs. postmenopausal women with microprolactinoma. Sixty-two women with microprolactinoma treated with cabergoline for at least 1 year and followed for 2 years after drug withdrawal were retrospectively selected. Patients were divided into two groups: 48 patients stopped cabergoline before menopause (“PRE” group), while 14 after menopause (“POST” group). Recurrence was defined by prolactin levels above normal, confirmed on two occasions. Overall, 39/62 women relapsed. Patients who relapsed apparently had higher prolactin before withdrawal (median 216.2, range 21.2–464.3 mIU/L) compared with those in long-term remission (94.3, 29.7–402.8 mIU/L; p < 0.05), and the risk of recurrence seemed lower in POST women (4/14, 29%) than in PRE ones (35/48, 73%, p < 0.005, OR 0.149, 95% CI 0.040–0.558). However, none of the factors (prolactin before withdrawal, menopausal status, treatment duration, complete adenoma regression) showed a correlation with recurrence risk in multivariate analysis. The best strategy able to optimize CBG treatment and withdrawal’s outcomes is still to be defined in microprolactinomas. Postmenopausal status cannot reliably predict long-term remission, and follow-up is needed also in women of this age.

Regression of a nonfunctioning pituitary macroadenoma on the CDK4/6 inhibitor palbociclib: case report

A 71-year-old female patient was referred in 2013 for evaluation of an asymptomatic nonsecreting pituitary adenoma. The adenoma, measuring 13 mm in height by 10 mm in width, was discovered incidentally on imaging in 2012. Biochemical testing demonstrated a nonfunctioning adenoma. Given the relatively small lesion size and the lack of symptoms, observation was preferred over surgical intervention. The patient was monitored with routine MRI, which until 2016 demonstrated minimal growth. In early 2016, the patient developed recurrence of metastatic breast cancer and was treated with palbociclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor. This inhibitor acts on a pathway believed to be involved in pituitary adenoma tumorigenesis. One year after starting palbociclib, routine imaging demonstrated significant regression of her pituitary adenoma. The authors hypothesize that inhibition of the CDK4/6 pathway by palbociclib contributed to adenoma regression in this patient, and that palbociclib may represent a possible adjuvant therapy for the treatment of nonfunctioning pituitary adenomas.

Association of Sulindac and Erlotinib vs Placebo With Colorectal Neoplasia in Familial Adenomatous Polyposis

Patients with familial adenomatous polyposis (FAP) are at markedly increased risk for colorectal polyps and cancer. A combination of sulindac and erlotinib led to a 71% reduction in duodenal polyp burden in a phase 2 trial. To evaluate effect of sulindac and erlotinib on colorectal adenoma regression in patients with FAP. Prespecified secondary analysis for colorectal adenoma regression was carried out using data from a double-blind, randomized, placebo-controlled trial, enrolling 92 patients with FAP, conducted from July 2010 to June 2014 in Salt Lake City, Utah. Patients were randomized to sulindac, 150 mg twice daily, and erlotinib, 75 mg daily (n = 46), vs placebo (n = 46) for 6 months. The total number of polyps in the intact colorectum, ileal pouch anal anastomosis, or ileo-rectum were recorded at baseline and 6 months. The primary outcomes were change in total colorectal polyp count and percentage change in colorectal polyps, following 6 months of treatment. Eighty-two randomized patients (mean [SD] age, 40 [13] years; 49 [60%] women) had colorectal polyp count data available for this secondary analysis: 22 with intact colon, 44 with ileal pouch anal anastomosis and 16 with ileo-rectal anastomosis; 41 patients received sulindac/erlotinib and 41 placebo. The total colorectal polyp count was significantly different between the placebo and sulindac-erlotinib group at 6 months in patients with net percentage change of 69.4% in those with an intact colorectum compared with placebo (95% CI, 28.8%-109.2%; P = .009). In this double-blind, placebo-controlled, randomized trial we showed that combination treatment with sulindac and erlotinib compared with placebo resulted in significantly lower colorectal polyp burden after 6 months of treatment. There was a reduction in polyp burden in both those with an entire colorectum and those with only a rectal pouch or rectum. clinicaltrials.gov Identifier: NCT01187901.

Abstract 1349: NSAIDs: Multiple roles in multiple environments

Abstract Non steroidal drugs are mainly known for their activities and use as anti-inflammatory, antipyretic compounds. But, in recent observations, they are exposed to use as an effective alternative compounds to prevent or stimulate different metabolic activities and help in preventing various neoplastic progression. They have specific role in controlling estrogen metabolism during breast cancer progression. Sometimes, they are used as an apoptotic induction in various cancers. Their role in hypoxia induced proliferation is also showing promising results. Different NSAIDs will help to induce the activities of various tumor suppressor genes. As chronic inflammation increases the risk for various cancers, therefore, it is important to eliminate inflammation through anti-Inflammatory compounds where NSAIDs are playing a vital role. Most of them are acting to prevent inflammation either via selective or non-selective COX based mechanism. The non-selective COX inhibitor sulindac and the COX-2 selective inhibitor etodolac etc. have been shown to prevent the formation and cause regression of adenomas in patients with familial polyposis. Unfortunately, COX-1 and/or COX-2 inhibition and depletion of physiologically important prostaglandins is associated with gastrointestinal, renal and cardiovascular toxicities that limit the use of NSAIDs and COX-2 inhibitors for cancer chemoprevention In this particular study, we are using various NSAIDs in a radiation-induced estogren treated breast cancer model to establish their role in differential expression of various cancer related genes selected from different cell cycle pathways microarray. Selection of biomarkers from these altered genes will help to develop a valid strategy for cancer prevention through precision based molecular targeted therapy. Supported by Office of Academic Affairs, Honors Program, COBI, Hostos-CUNY, NY, USA (DR) and Tarapacá University, Arica, Chile (GMC). Citation Format: Gloria M. Calaf, Debasish Roy. NSAIDs: Multiple roles in multiple environments [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1349. doi:10.1158/1538-7445.AM2017-1349

Abstract IA11: Chemoprevention in hereditary GI cancer syndromes

Abstract IA11: Chemoprevention in hereditary GI cancer syndromes

The interaction between the Wnt/β-catenin signaling cascade and PKG activation in cancer.

The activation of the Wnt/β-catenin signaling cascade has been well studied and documented in colorectal cancer (CRC). The long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) has been shown to reduce the incidence and risk of death from CRC in numerous epidemiological studies. The NSAID sulindac has also been reported to cause regression of precancerous adenomas in individuals with familial adenomatous polyposis who are at high risk of developing CRC. The mechanism responsible for cancer chemopreventive activity of NSAIDs is not well understood but may be unrelated to their cyclooxygenase inhibitory activity. Emerging evidence suggests that sulindac inhibits the growth of colon tumor cells by suppressing the activity of certain phosphodiesterase isozymes to activate cGMP-dependent protein kinase, PKG, through the elevation of the second messenger cyclic guanosine monophosphote, cGMP. PKG activation has been shown to inhibit the nuclear translocation of β-catenin, reduce β-catenin mRNA and protein levels, and suppress the transcriptional activity of β-catenin. This review describes the relationship between the Wnt/β-catenin signaling cascade and the activation of PKG through PDE inhibition and elevation of intracellular cGMP levels.

Chemoprevention of hereditary colon cancers: time for new strategies.

Colorectal cancer (CRC) is potentially preventable. Chemoprevention, a focus of research for the past three decades, aims to prevent or delay the onset of cancer through the regression or prevention of colonic adenomas. Ideal pharmacological agents for chemoprevention should be cheap and nontoxic. Although data indicate that aspirin can reduce the risk of CRC in the general population, the highest return from chemopreventive strategies would be expected in patients with the highest risk of developing the disease, particularly those with a defined hereditary predisposition. Despite compelling data showing that a large number of chemopreventive agents show promise in preclinical CRC models, clinical studies have yielded conflicting results. This Review provides a historical and methodological perspective of chemoprevention in familial adenomatous polyposis and Lynch syndrome, and summarizes the current status of CRC chemoprevention in humans. Our goal is to critically focus on important issues of trial design, with particular attention on the choice of appropriate trial end points, how such end points should be measured, and which patients are the ideal candidates to be included in a chemopreventive trial.

Effect of Sulindac and Erlotinib vs Placebo on Duodenal Neoplasia in Familial Adenomatous Polyposis: A Randomized Clinical Trial.

Patients with familial adenomatous polyposis (FAP) are at markedly increased risk for duodenal polyps and cancer. Surgical and endoscopic management of duodenal neoplasia is difficult and chemoprevention has not been successful. To evaluate the effect of a combination of sulindac and erlotinib on duodenal adenoma regression in patients with FAP. Double-blind, randomized, placebo-controlled trial, enrolling 92 participants with FAP, conducted from July 2010 through June 2014 at Huntsman Cancer Institute in Salt Lake City, Utah. Participants with FAP were randomized to sulindac (150 mg) twice daily and erlotinib (75 mg) daily (n = 46) vs placebo (n = 46) for 6 months. The total number and diameter of polyps in the proximal duodenum were mapped at baseline and 6 months. The primary outcome was change in total polyp burden at 6 months. Polyp burden was calculated as the sum of the diameters of polyps. The secondary outcomes were change in total duodenal polyp count, change in duodenal polyp burden or count stratified by genotype and initial polyp burden, and percentage of change from baseline in duodenal polyp burden. Ninety-two participants (mean age, 41 years [range, 24-55]; women, 56 [61%]) were randomized when the trial was stopped by the external data and safety monitoring board because the second preplanned interim analysis met the prespecified stopping rule for superiority. Grade 1 and 2 adverse events were more common in the sulindac-erlotinib group, with an acne-like rash observed in 87% of participants receiving treatment and 20% of participants receiving placebo (P < .001). Only 2 participants experienced grade 3 adverse events. [table: see text]. Among participants with FAP, the use of sulindac and erlotinib compared with placebo resulted in a lower duodenal polyp burden after 6 months. Adverse events may limit the use of these medications at the doses used in this study. Further research is necessary to evaluate these preliminary findings in a larger study population with longer follow-up to determine whether the observed effects will result in improved clinical outcomes. clinicaltrials.gov Identifier: NCT 01187901.

Highlights from Recent Cancer Literature

Highlights from Recent Cancer Literature

Targeted therapy of colorectal neoplasia with rapamycin in peptide-labeled pegylated octadecyl lithocholate micelles

Many powerful drugs have limited clinical utility because of poor water solubility and high systemic toxicity. Here, we formulated a targeted nanomedicine, rapamycin encapsulated in pegylated octadecyl lithocholate micelles labeled with a new ligand for colorectal neoplasia, LTTHYKL peptide. CPC;Apc mice that spontaneously develop colonic adenomas were treated with free rapamycin, plain rapamycin micelles, and peptide-labeled rapamycin micelles via intraperitoneal injection for 35days. Endoscopy was performed to monitor adenoma regression in vivo. We observed complete adenoma regression at the end of therapy. The mean regression rate for peptide-labeled rapamycin micelles was significantly greater than that for plain rapamycin micelles, P<0.01. On immunohistochemistry, we observed a significant reduction in phospho-S6 but not β-catenin expression and reduced tumor cell proliferation, suggesting greater inhibition of downstream mTOR signaling. We observed significantly reduced renal toxicity for peptide-labeled rapamycin micelles compared to that of free drug, and no other toxicities were found on chemistries. Together, this unique targeted micelle represents a potential therapeutic for colorectal neoplasia with comparable therapeutic efficacy to rapamycin free drug and significantly less systemic toxicity.

Lack of anti-tumor activity with the β-catenin expression inhibitor EZN-3892 in the C57BL/6J Min/+ model of intestinal carcinogenesis

BackgroundPreviously, we showed that short-term inhibition of β-catenin expression and reversal of aberrant β-catenin subcellular localization by the selective COX-2 inhibitor celecoxib is associated with adenoma regression in the C57BL/6J Min/+ mouse. Conversly, long-term administration resulted in tumor resistance, leading us to investigate alternative methods for selective β-catenin chemoprevention. In this study, we hypothesized that disruption of β-catenin expression by EZN-3892, a selective locked nucleic acid (LNA)-based β-catenin inhibitor, would counteract the tumorigenic effect of Apc loss in Min/+ adenomas while preserving normal intestinal function. Materials and methodsC57BL/6J Apc+/+ wild-type (WT) and Min/+ mice were treated with the maximum tolerated dose (MTD) of EZN-3892 (30mg/kg). Drug effect on tumor numbers, β-catenin protein expression, and nuclear β-catenin localization were determined. ResultsAlthough the tumor phenotype and β-catenin nuclear localization in Min/+ mice did not change following drug administration, we observed a decrease in β-catenin expression levels in the mature intestinal tissue of treated Min/+ and WT mice, providing proof of principle regarding successful delivery of the LNA-based antisense vehicle. Higher doses of EZN-3892 resulted in fatal outcomes in Min/+ mice, likely due to β-catenin ablation in the intestinal tissue and loss of function. ConclusionsOur data support the critical role of Wnt/β-catenin signaling in maintaining intestinal homeostasis and highlight the challenges of effective drug delivery to target disease without permanent toxicity to normal cellular function.

Regression of Colonic Adenomas After Treatment With Sulindac in Familial Adenomatous Polyposis: A Case With a 2-Year Follow-up Without a Prophylactic Colectomy.

Familial adenomatous polyposis (FAP) is an autosomal dominant disorder characterized by hundreds of colorectal adenomatous polyps that progress to colorectal cancer. Management of patients with FAP is with a total colectomy. Chemopreventive strategies have been studied in FAP patients in an effort to delay the development of adenomas in the upper and the lower gastrointestinal tract and to prevent recurrence of adenomas in the retained rectum of patients after prophylactic surgery. Sulindac, a nonsteroidal anti-inflammatory drug, causes regression of colorectal adenomas in the retained rectal segment of FAP patients. However, evidence regarding long-term use of this therapy and its effect on the intact colon has been insufficient. We report a case in which the long-term use of sulindac was effective in reducing the size and the number of colonic polyps in patients with FAP without a prophylactic colectomy and polypectomy; we also present a review of the literature.

Regression of hepatocellular adenomas with strict dietary therapy in patients with glycogen storage disease type I.

Hepatocellular adenomas (HCAs) are a common complication in patients with glycogen storage disease type I (GSD I). In this series, we report regression of HCAs in a cohort of patients who achieved metabolic control with strict dietary therapy. A retrospective review of the clinical records for all patients with GSD I was performed at our institution. All available imaging studies were reviewed in patients with reported regression of HCAs in the medical record. The charts of 163 patients with GSD Ia and 42 patients with GSD Ib were reviewed, and HCAs were documented in 47 subjects (43 Ia/4 Ib). After review of all available imaging studies, eight patients met criteria of being followed with both magnetic resonance imaging and ultrasound and were found to show evidence of regression of HCAs. In these individuals, regression of the HCAs occurred once metabolic control was obtained, as determined by decreasing levels of serum triglyceride levels. The average triglyceride level in all patients prior to regression of HCAs was 753mg/dL (SD ± 293). The average serum triglyceride level in all patients at the time of regression of HCAs was 340mg/dL (SD ± 164). These findings suggest that strict dietary therapy may cause regression of HCAs. If HCAs are documented in a patient with suboptimal metabolic control, intensive medical therapy may be an alternative to surgical intervention in some individuals.

Multimodal Imaging of Growth and Rapamycin-Induced Regression of Colonic Adenomas in Apc Mutation-Dependent Mouse

We demonstrate that rapamycin can induce regression of adenomatous polyposis coli (Apc) mutation-dependent colonic adenomas in genetically engineered mice (CPC;Apc). An endoscope was used to visualize adenomas in CPC;Apc mice weekly for 10 weeks. The lesion surface areas were measured using a distance gauge and digitally generated grid. Coronal scans were performed on magnetic resonance imaging (MRI) to localize adenomas, and tumor volumes were measured from regions of interest drawn on consecutive axial scans. Rapamycin (5 mg/kg) was administered intraperitoneally daily for 5 weeks. Endoscopy and MRI were performed weekly to monitor adenoma regression. Caliper measurements and immunohistochemistry (IHC) were performed on adenomas postmortem. Dimensions from n = 30 adenomas in n = 7 animals were measured. Adenoma surface areas on endoscopy correlated with volumes on MRI and with postmortem caliper measurements, R(2) = 0.84 and R(2) = 0.81, respectively. The mean adenoma doubling times on endoscopy and MRI were 0.95 ± 0.14 and 1.21 ± 0.16 weeks, respectively. The minimum detectable adenoma surface area and volume on endoscopy and MRI was 0.69 mm(2) and 1.76 mm(3), respectively. On histology, the rapamycin-treated adenomas showed limited regions of dysplasia. Rapamycin therapy resulted in much lower mammalian target of rapamycin signaling and cell proliferation. Lower expression of phospho-S6 and reduced numbers of Ki67-positive cells were seen on IHC compared to vehicle-treated lesions. Endoscopy can be validated by MRI as a robust methodology for quantitative monitoring of therapy, representing a promising approach for future preclinical efforts to assess utility of novel colorectal cancer prevention strategies.

The natural history of colorectal adenomas and early cancer

Adenomas represent the morphological precursors of the vast majority of colorectal cancers: although every adenoma has the capacity of malignant evolution, most adenomas stabilize their progression or even regress. Pathological factors are predictive of the natural history of adenomas in terms of potential and time interval for becoming malignant. Regression of adenomas is histologically well established, but it is thought to be a dynamic process, with cycling phases of regression and growth. Colorectal carcinoma invading the submucosa but not the muscular layer represents the earliest form of clinically relevant colorectal cancer. Grade of differentiation of carcinoma, lymphovascular invasion, and state of the resection margin predict the risk of metastasis. Microstaging of invasive cancer together with tumuor budding allow the metastatic risk to be further stratified into minimal, low, and high. Two distinct profiles are identifiable in the natural history of cancerous adenomas: blocking the growth of early cancer and allowing its progression towards advanced cancer. Thus, biomarkers to distinguish between progressive and non-progressive pT1 neoplasia are needed.

Inhibition of cyclooxygenase‐2 causes regression of gastric adenomas in trefoil factor 1 deficient mice

Cyclooxygenase-2 (Cox-2) expression is a marker of reduced survival in gastric cancer patients, and inhibition of Cox-2 suppresses gastrointestinal carcinogenesis in experimental animal models. To investigate the role of Cox-2 in gastric carcinogenesis in vivo, we utilized trefoil factor 1 (Tff1) deficient mice, which model the neoplastic process of the stomach by developing gastric adenomas with full penetrance. These tumors express Cox-2 protein and mRNA, and we have now investigated the effects of genetic deletion of the mouse Cox-2 gene [also known as prostaglandin-endoperoxide synthase 2 (Ptgs2)] and a Cox-2 selective drug celecoxib. Our results show that genetic deletion of Cox-2 in the Tff1 deleted background resulted in reduced adenoma size and ulceration with a chronic inflammatory reaction at the site of the adenoma. To characterize the effect of Cox-2 inhibition in more detail, mice that had already developed an adenoma were fed with celecoxib for 8-14 weeks, which resulted in disruption of the adenoma that ranged from superficial erosion to deep ulcerated destruction accompanied with chronic inflammation. Importantly, mice fed with celecoxib for 16 weeks, followed by control food for 9 weeks, redeveloped a complete adenoma with no detectable inflammatory process. Finally, we determined the identity of the Cox-2 expressing cells and found them to be fibroblasts. Our results show that inhibition of Cox-2 is sufficient to reversibly disrupt gastric adenomas in mice.

Cytokines, Inflammation and Colon Cancer

Patients with inflammatory bowel diseases, such as ulcerative colitis and Crohn's disease, are at increased risk of developing colon cancer, confirming that chronic inflammation predisposes to development of tumors. Moreover, it appears that colon cancers that do not develop as a complication of inflammatory bowel disease are also driven by inflammation, because it has been shown that regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) lowers the mortality from sporadic colon cancer and results in regression of adenomas in familial adenomatous polyposis (FAP) patients, who inherit a mutation in the Apc gene. Colorectal cancer therefore represents a paradigm for the link between inflammation and cancer. Inflammation is driven by soluble factors, cytokines and chemokines, which can be produced by tumor cells themselves or, more often, by the cells recruited to the tumor microenvironment. Inflammatory cytokines and chemokines promote growth of tumor cells, perturb their differentiation, and support the survival of cancer cells. Tumor cells become addicted to inflammatory stroma, suggesting that the tumor microenvironment represents an attractive target for preventive and therapeutic strategies. Proinflammatory cytokines, such as TNFα, IL-6 and IL-1β, or transcription factors that are required for signaling by these cytokines, including NF-κB and STATs, are indeed emerging as potential targets for anticancer therapy. TNFα antagonists are in phase I/II clinical trials and have been shown to be well tolerated in patients with solid tumors, and IL-1β antagonists that ameliorate several inflammatory disorders characterized by excessive IL-1β production, will likely follow. Therefore, development of drugs that normalize the tumor microenvironment or interrupt the crosstalk between the tumor and the tumor microenvironment is an important approach to the management of cancer.