ABSTRACT
BACKGROUND: In colon cancer, tumor deposits (TD) are considered in assigning prognosis and staging only in the absence of lymph node metastasis (i.e. stage III pN1c tumors). We aimed to evaluate the prognostic value of the presence and the number of TD in patients with stage III, node-positive colon cancer. PATIENTS AND METHODS: All participants from the CALGB/SWOG 80702 phase III trial were included in this post hoc analysis. Pathology reports were reviewed for the presence and the number of TD, lymphovascular and perineural invasion. Associations with disease-free survival (DFS) and overall survival (OS) were evaluated by multivariable Cox models adjusting for sex, treatment arm, T-stage, N-stage, lymphovascular invasion, perineural invasion and lymph node ratio. RESULTS: Overall, 2028 patients were included with 524 (26%) TD-positive and 1504 (74%) TD-negative tumors. Of the TD-positive patients, 80 (15.4%) were node negative (i.e. pN1c), 239 (46.1%) were pN1a/b (<4 positive lymph nodes) and 200 (38.5%) were pN2 (≥4 positive lymph nodes). The presence of TD was associated with poorer DFS [adjusted hazard ratio (aHR) = 1.63, 95% CI 1.33-1.98] and OS (aHR = 1.59, 95% CI 1.24-2.04). The negative effect of TD was observed for both pN1a/b and pN2 groups. Among TD-positive patients, the number of TD had a linear negative effect on DFS and OS. Combining TD and the number of lymph node metastases, 104 of 1470 (7.1%) pN1 patients were re-staged as pN2, with worse outcomes than patients confirmed as pN1 (3-year DFS rate: 65.4% versus 80.5%, P = 0.0003; 5-year OS rate: 87.9% versus 69.1%, P = <0.0001). DFS was not different between patients re-staged as pN2 and those initially staged as pN2 (3-year DFS rate: 65.4% versus 62.3%, P = 0.4895). CONCLUSION: Combining the number of TD and the number of lymph node metastases improved the prognostication accuracy of tumor-node-metastasis (TNM) staging.
Subject(s)
Colonic Neoplasms , Extranodal Extension , Colonic Neoplasms/pathology , Humans , Lymph Nodes/pathology , Lymphatic Metastasis , Neoplasm Staging , Prognosis , Retrospective StudiesABSTRACT
BACKGROUND: Patients undergoing surgery for soft tissue sarcoma have high morbidity rates, particularly after preoperative radiation therapy (RT). An enhanced recovery after surgery (ERAS) programme may improve perioperative outcomes in abdominal surgery. This study reported outcomes of an ERAS programme tailored to patients with soft tissue sarcoma. METHODS: A prospective ERAS protocol was implemented in 2015 at a high-volume sarcoma centre. Patients treated within the ERAS programme from 2015 to 2018 were case-matched retrospectively with patients treated between 2012 and 2018 without use of the protocol, matched by surgical site, surgeon, sarcoma histology and preoperative RT treatment. Postoperative outcomes, specifically wound complications and duration of hospital stay, were reported. RESULTS: In total, 234 patients treated within the ERAS programme were matched with 237 who were not. The ERAS group had lower wound dehiscence rates overall (2 of 234 (0·9 per cent) versus 31 of 237 (13·1 per cent); P < 0·001), after preoperative RT (0 of 41 versus 11 of 51; P = 0·004) and after extremity sarcoma surgery (0 of 54 versus 6 of 56; P = 0·040) compared with the non-ERAS group. Rates of postoperative ileus or obstruction were lower in the ERAS group (21 of 234 (9·9 per cent) versus 40 of 237 (16·9 per cent); P = 0·016) and in those with retroperitoneal sarcoma (4 of 36 versus 15 of 36; P = 0·007). Duration of hospital stay was shorter in the ERAS group (median 5 (range 0-36) versus 6 (0-67) days; P = 0·003). CONCLUSION: Treatment within an ERAS protocol for patients with soft tissue sarcoma was associated with lower morbidity and shorter hospital stay.
ANTECEDENTES: Los pacientes sometidos a cirugía por sarcoma de tejido blando (soft tissue sarcoma, STS) tienen altas tasas de morbilidad, particularmente después de la radioterapia preoperatoria (RT). El programa de recuperación intensificada después de la cirugía (enhanced recovery after surgery, ERAS) puede mejorar los resultados perioperatorios en la cirugía abdominal. Este estudio analizó los resultados de un programa ERAS diseñado para pacientes con STS. MÉTODOS: Se implementó un protocolo prospectivo ERAS en el año 2015 en un centro de alto volumen de sarcomas. Los pacientes en ERAS desde 2015 hasta 2018 fueron emparejados retrospectivamente con pacientes sin ERAS desde 2012 hasta 2018, según la localización quirúrgica, el cirujano, la histología del sarcoma y el tratamiento con RT preoperatoria. Se analizaron los resultados postoperatorios, específicamente las complicaciones de la herida y la duración de la estancia hospitalaria (length of stay, LOS). RESULTADOS: En total, 234 pacientes tratados con ERAS se compararon con 237 pacientes no tratados con ERAS. Los pacientes con ERAS tuvieron tasas globales más bajas de dehiscencia de la herida (2 (0,9%) versus 31 (13,1%), P < 0,001)), después de la RT preoperatoria (0 versus 11 (21,6%), P = 0,004)), y después de la cirugía de STS de extremidades (0 versus 6 (0,7%), P = 0,04)) en comparación con los pacientes no ERAS. Las tasas de íleo u obstrucción postoperatorias fueron más bajas en el grupo ERAS (21 (9,9%) versus 40 (16,9%), P = 0,02)) y en aquellos pacientes con sarcoma retroperitoneal (4 (11,1%) versus 15 (41,7%), P = 0,007)). La mediana (rango) de la LOS fue más corta en los pacientes con ERAS que fue de 5 (0-36) días que en los pacientes sin ERAS que fue de 6 (0-67) días (P = 0,003). CONCLUSIÓN: ERAS para pacientes con STS se asoció con una menor morbilidad y una estancia hospitalaria más corta.
Subject(s)
Enhanced Recovery After Surgery , Sarcoma/surgery , Critical Pathways , Female , Humans , Length of Stay/statistics & numerical data , Male , Middle Aged , Postoperative Complications/epidemiology , Postoperative Complications/etiology , Retrospective StudiesABSTRACT
BACKGROUND: Although cytoreductive surgery has been shown to be beneficial in carefully selected patients with metastatic gastrointestinal stromal tumours (GISTs) treated with tyrosine kinase inhibitors (TKIs), factors predictive of postoperative morbidity have not been investigated previously. METHODS: A surgical complexity score for GIST metastasectomy (GM-SCS) composed of patient-related and surgical factors was assigned retrospectively to patients with metastatic GIST treated with TKI therapy and surgery at two institutions between 2002 and 2014. The ability of clinicopathological factors and GM-SCS to predict postoperative morbidity was assessed by means of a multivariable logistic regression model. Postoperative complications were categorized using the Clavien-Dindo classification. RESULTS: Some 400 operations on 323 patients with metastatic GIST on TKIs were included. Complications were observed following 110 operations (27·5 per cent) including 70 major complications (grade III-V) (17·5 per cent of 400 operations). Patients were divided into low (5 points or less; 100 patients, 25·0 per cent), intermediate (6-9 points; 191, 47·8 per cent) and high (at least 10 points; 109, 27·3 per cent) complexity scoring groups based on the GM-SCS. An intermediate (odds ratio (OR) 2·88; P = 0·008) and high (OR 5·40; P < 0·001) GM-SCS were independent predictors of overall complications, whereas only a high GM-SCS was independently predictive of a major complication (OR 3·65; P = 0·018). Metastatic mitotic index was also an independent predictor of overall complications (OR 2·55; P = 0·047). GM-SCS did not predict progression-free or overall survival. CONCLUSION: A gastrointestinal stromal tumour metastastectomy surgical complexity score can predict morbidity, which may help in preoperative risk stratification and optimal treatment planning.
Subject(s)
Antineoplastic Agents/therapeutic use , Cytoreduction Surgical Procedures , Gastrointestinal Neoplasms/surgery , Gastrointestinal Stromal Tumors/surgery , Imatinib Mesylate/therapeutic use , Protein-Tyrosine Kinases/antagonists & inhibitors , Aged , Combined Modality Therapy/adverse effects , Combined Modality Therapy/methods , Cytoreduction Surgical Procedures/adverse effects , Gastrointestinal Neoplasms/pathology , Gastrointestinal Neoplasms/therapy , Gastrointestinal Stromal Tumors/pathology , Gastrointestinal Stromal Tumors/therapy , Humans , Metastasectomy , Middle Aged , Risk FactorsABSTRACT
The risk of several cancers, including colorectal cancer, is increased in patients with obesity and type 2 diabetes, conditions characterised by hyperinsulinaemia and insulin resistance. Because hyperinsulinaemia itself is an independent risk factor for cancer development, we examined tissue-specific insulin action in intestinal tumour formation. In vitro, insulin increased proliferation of intestinal tumour epithelial cells by almost two-fold in primary culture of tumour cells from ApcMin/+ mice. Surprisingly, targeted deletion of insulin receptors in intestinal epithelial cells in ApcMin/+ mice did not change intestinal tumour number or size distribution on either a low or high-fat diet. We therefore asked whether cells in the tumour stroma might explain the association between tumour formation and insulin resistance. To this end, we generated ApcMin/+ mice with loss of insulin receptors in vascular endothelial cells. Strikingly, these mice had 42% more intestinal tumours than controls, no change in tumour angiogenesis, but increased expression of vascular cell adhesion molecule-1 (VCAM-1) in primary culture of tumour endothelial cells. Insulin decreased VCAM-1 expression and leukocyte adhesion in quiescent tumour endothelial cells with intact insulin receptors and partly prevented increases in VCAM-1 and leukocyte adhesion after treatment with tumour necrosis factor-α. Knockout of insulin receptors in endothelial cells also increased leukocyte adhesion in mesenteric venules and increased the frequency of neutrophils in tumours. We conclude that although insulin is mitogenic for intestinal tumour cells in vitro, impaired insulin action in the tumour microenvironment may be more important in conditions where hyperinsulinaemia is secondary to insulin resistance. Insulin resistance in tumour endothelial cells produces an activated, proinflammatory state that promotes tumorigenesis. Improvement of endothelial dysfunction may reduce colorectal cancer risk in patients with obesity and type 2 diabetes.
Subject(s)
Carcinogenesis/metabolism , Colorectal Neoplasms/metabolism , Endothelial Cells/metabolism , Insulin Resistance , Animals , Carcinogenesis/genetics , Carcinogenesis/pathology , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Endothelial Cells/pathology , Gene Knockdown Techniques , Insulin/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Receptor, Insulin/genetics , Receptor, Insulin/metabolism , Signal Transduction , Tumor Microenvironment , Vascular Cell Adhesion Molecule-1/biosynthesisABSTRACT
BACKGROUND: Observational studies suggest that higher levels of 25-hydroxyvitamin D3 (25(OH)D) are associated with a reduced risk of colorectal cancer and improved survival of colorectal cancer patients. However, the influence of vitamin D status on cancer recurrence and survival of patients with stage III colon cancer is unknown. PATIENTS AND METHODS: We prospectively examined the influence of post-diagnosis predicted plasma 25(OH)D on outcome among 1016 patients with stage III colon cancer who were enrolled in a National Cancer Institute-sponsored adjuvant therapy trial (CALGB 89803). Predicted 25(OH)D scores were computed using validated regression models. We examined the influence of predicted 25(OH)D scores on cancer recurrence and mortality (disease-free survival; DFS) using Cox proportional hazards. RESULTS: Patients in the highest quintile of predicted 25(OH)D score had an adjusted hazard ratio (HR) for colon cancer recurrence or mortality (DFS) of 0.62 (95% confidence interval [CI], 0.44-0.86), compared with those in the lowest quintile (Ptrend = 0.005). Higher predicted 25(OH)D score was also associated with a significant improvement in recurrence-free survival and overall survival (Ptrend = 0.01 and 0.0004, respectively). The benefit associated with higher predicted 25(OH)D score appeared consistent across predictors of cancer outcome and strata of molecular tumor characteristics, including microsatellite instability and KRAS, BRAF, PIK3CA, and TP53 mutation status. CONCLUSION: Higher predicted 25(OH)D levels after a diagnosis of stage III colon cancer may be associated with decreased recurrence and improved survival. Clinical trials assessing the benefit of vitamin D supplementation in the adjuvant setting are warranted. CLINICALTRIALS.GOV IDENTIFIER: NCT00003835.
Subject(s)
Colonic Neoplasms/pathology , Neoplasm Recurrence, Local , Vitamin D/blood , Adult , Aged , Aged, 80 and over , Colonic Neoplasms/blood , Colonic Neoplasms/mortality , Disease-Free Survival , Female , Humans , Male , Middle Aged , Prospective StudiesABSTRACT
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.
Subject(s)
Apoptosis/drug effects , Colorectal Neoplasms/pathology , Estradiol/analogs & derivatives , Estradiol/pharmacology , Tumor Cells, Cultured/drug effects , Tumor Suppressor Protein p53/metabolism , 2-Methoxyestradiol , Blotting, Western , Colorectal Neoplasms/genetics , Colorectal Neoplasms/metabolism , Cyclin-Dependent Kinase Inhibitor p21 , Cyclins/metabolism , Estrogen Receptor alpha , Estrogen Receptor beta , Humans , Poly(ADP-ribose) Polymerases/metabolism , Receptors, Estrogen/metabolism , Tumor Cells, Cultured/metabolismABSTRACT
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.
Subject(s)
Adenoma/metabolism , Adenomatous Polyposis Coli Protein/genetics , Adherens Junctions/chemistry , Trans-Activators , Alleles , Animals , Cadherins/metabolism , Cell Adhesion , Cell Membrane/metabolism , Cell Nucleus/metabolism , Cytoskeletal Proteins/metabolism , Cytosol/metabolism , Enterocytes/metabolism , Female , Gene Deletion , Genes, Dominant , Heterozygote , Immunoblotting , Immunohistochemistry , Mice , Mice, Mutant Strains , Mutation , Phosphorylation , Precipitin Tests , Protein Binding , Subcellular Fractions , Tyrosine/metabolism , beta CateninABSTRACT
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.
Subject(s)
Estrogens/physiology , Intestinal Neoplasms/metabolism , Receptors, Estrogen/biosynthesis , Adenomatous Polyposis Coli Protein , Animals , Cytoskeletal Proteins/genetics , Enterocytes/metabolism , Estradiol/pharmacology , Estrogen Receptor alpha , Estrogen Receptor beta , Estrogen Replacement Therapy , Female , Genes, APC/genetics , Germ-Line Mutation , Intestinal Mucosa/metabolism , Intestinal Neoplasms/etiology , Intestinal Neoplasms/genetics , Mice , Mice, Inbred C57BL , OvariectomyABSTRACT
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.
Subject(s)
Anticarcinogenic Agents/pharmacology , Catechin/pharmacology , Intestinal Neoplasms/prevention & control , Protein-Tyrosine Kinases/antagonists & inhibitors , 3T3 Cells , Animals , Cell Division/drug effects , Cytoskeleton/drug effects , Enterocytes/drug effects , Enterocytes/enzymology , Enzyme Activation , Female , Focal Adhesion Kinase 1 , Focal Adhesion Protein-Tyrosine Kinases , Humans , Integrins/physiology , Intestinal Neoplasms/pathology , Mice , Mice, Inbred C57BL , Neoplasm Invasiveness , Phosphorylation/drug effects , Protein-Tyrosine Kinases/metabolism , Signal Transduction/drug effects , Signal Transduction/physiology , Stereoisomerism , Tumor Cells, Cultured/drug effects , Tyrosine/metabolismABSTRACT
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.
Subject(s)
Carcinoma, Squamous Cell/surgery , Lymph Node Excision , Mohs Surgery , Skin Neoplasms/surgery , Aged , Carcinoma, Squamous Cell/pathology , Humans , Lymphatic Metastasis , Male , Neoplasm Staging , Risk Factors , Skin Neoplasms/pathologyABSTRACT
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.
Subject(s)
Adenomatous Polyposis Coli/pathology , Intestinal Neoplasms/prevention & control , Phenols/pharmacology , Plants/chemistry , Trans-Activators , Adenomatous Polyposis Coli/metabolism , Animals , Cell Division/drug effects , Cytoskeletal Proteins/metabolism , Disease Models, Animal , Enterocytes/cytology , Enterocytes/drug effects , Mice , Mice, Inbred C57BL , beta CateninABSTRACT
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.
Subject(s)
Antineoplastic Agents/pharmacology , Curcumin/pharmacology , Immune System/cytology , Immune System/drug effects , Intestinal Mucosa/pathology , Intestinal Neoplasms/prevention & control , Intestines/cytology , Intestines/drug effects , Adenomatous Polyposis Coli Protein , Animals , B-Lymphocytes/drug effects , B-Lymphocytes/pathology , CD4 Lymphocyte Count/drug effects , CD4-Positive T-Lymphocytes/pathology , Cytoskeletal Proteins/genetics , Germ-Line Mutation , Immunohistochemistry , Intestinal Mucosa/drug effects , Intestinal Neoplasms/genetics , Lymphocyte Count/drug effects , Mice , Mice, Inbred C57BL , Mice, Mutant Strains/geneticsABSTRACT
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.
Subject(s)
Antineoplastic Agents/pharmacology , Colonic Neoplasms/prevention & control , Integrins/physiology , Proteins , Signal Transduction/drug effects , Actins/drug effects , Actins/metabolism , Caffeic Acids/pharmacology , Cell Movement/drug effects , Colonic Neoplasms/pathology , Colonic Neoplasms/physiopathology , Crk-Associated Substrate Protein , Focal Adhesion Kinase 1 , Focal Adhesion Protein-Tyrosine Kinases , Humans , Phenylethyl Alcohol/analogs & derivatives , Phenylethyl Alcohol/pharmacology , Phosphoproteins/drug effects , Phosphoproteins/metabolism , Phosphorylation/drug effects , Protein-Tyrosine Kinases/drug effects , Protein-Tyrosine Kinases/metabolism , Retinoblastoma-Like Protein p130 , Sulindac/analogs & derivatives , Sulindac/pharmacology , Tumor Cells, CulturedABSTRACT
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.
Subject(s)
Chenodeoxycholic Acid/toxicity , Cholagogues and Choleretics/toxicity , Duodenal Neoplasms/chemically induced , Trans-Activators , Adenomatous Polyposis Coli , Adenomatous Polyposis Coli Protein , Animals , Carcinogenicity Tests , Cytoskeletal Proteins/metabolism , Dinoprostone/metabolism , Disease Models, Animal , Duodenal Neoplasms/genetics , Duodenum/drug effects , Duodenum/metabolism , Female , Mice , beta CateninSubject(s)
Colorectal Neoplasms/complications , Colorectal Neoplasms/surgery , Hemangioma/complications , Hemangioma/surgery , Thrombocytopenia/etiology , Thrombocytopenia/surgery , Adult , Colorectal Neoplasms/blood , Colorectal Neoplasms/pathology , Hemangioma/blood , Hemangioma/pathology , Humans , Male , Syndrome , Thrombocytopenia/blood , Thrombocytopenia/pathology , Time Factors , Treatment OutcomeABSTRACT
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.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Genes, APC , Intestines/cytology , Mutation , Sulindac/pharmacology , Trans-Activators , Adenomatous Polyposis Coli/genetics , Animals , Cell Movement/drug effects , Cytoskeletal Proteins/metabolism , Female , Genotype , Intestinal Mucosa/pathology , Mice , Phenotype , Precancerous Conditions/genetics , Precancerous Conditions/pathology , beta CateninABSTRACT
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.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Colorectal Neoplasms/prevention & control , Cyclooxygenase Inhibitors/therapeutic use , Isoenzymes/metabolism , Prostaglandin-Endoperoxide Synthases/metabolism , Animals , Arachidonic Acid/metabolism , Colorectal Neoplasms/metabolism , Cyclooxygenase 2 , Cyclooxygenase 2 Inhibitors , Humans , Membrane Proteins , RatsABSTRACT
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.
Subject(s)
Cell Transformation, Neoplastic , Cytoskeletal Proteins/physiology , Intestinal Neoplasms , Adenomatous Polyposis Coli Protein , Animals , Disease Models, Animal , Gene Expression Regulation, Neoplastic , Genes, APC , Humans , Intestinal Neoplasms/genetics , Intestinal Neoplasms/pathology , Intestinal Neoplasms/physiopathology , Neoplasm Proteins/physiologyABSTRACT
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.