cyclin-d1 and Adenocarcinoma--Mucinous

Intraductal papillary neoplasm of the bile duct (IPNB) is characterized by exophytic proliferation of neoplastic epithelial cells with fibrovascular stalks in bile duct lumen, mucin hypersecretion, and considerable dilatation or multilocular changes of the affected bile ducts. A mucin-producing bile duct tumor is an IPNB with excessive mucin production and clinical symptoms. Herein, the phenotypes as well as the tumorigenesis and progression of IPNB are reviewed with immunohistochemical assistance. The tumors are subdivided into three phenotypes: pancreatobiliary, intestinal, and gastric. About half of IPNB cases are of the pancreatobiliary type, and the remaining half are of the intestinal type. Aberrant expression of CDX2 with MUC2 and CK20 is related to the development of intestinal metaplasia. Inactivation of P16INK4a and nuclear expression of beta-catenin are related to the development of IPNB. Decreased expression of membranous beta-catenin and E-cadherin and aberrant expression of MMP-7 and -9 and of MUC1 are related to invasion of IPNB with tubular adenocarcinoma, whereas MUC2 is involved in the invasion of IPNB with mucinous carcinoma. IPNB can be regarded as a counterpart of intraductal papillary mucinous neoplasm (IPMN) of the pancreas, particularly the main duct type. More comparative studies between IPNB and pancreatic IPMN are recommended for further analysis of these papillary neoplasms.

Topics: Adenocarcinoma, Mucinous; beta Catenin; Bile Duct Neoplasms; Cadherins; Carcinoma, Ductal; Carcinoma, Papillary; CDX2 Transcription Factor; Cholangiocarcinoma; Cyclin D1; Disease Progression; Homeodomain Proteins; Humans; Immunohistochemistry; Keratin-20; Matrix Metalloproteinase 7; Matrix Metalloproteinase 9; Mucin-1; Mucin-2; Mucins; Neoplasm Invasiveness; Pancreatic Neoplasms; Phenotype

For treatment of metastatic colorectal cancer, the dynamics of tumor growth is an important factor for treatment decision. However, it is difficult to evaluate the dynamics of tumor growth, especially those of synchronous metastatic diseases. This study aimed to find some indicators related to tumor proliferation to judge the dynamics of tumor progression. The pathological reports and clinical data of 1205 patients with metastatic colorectal cancer were retrospectively reviewed; 75 patients with known relapse time after radical resection were included, and the expression of proliferation-associated proteins was detected by immunohistochemistry. Relapse-free time (RFT) from radical resection to relapse was obtained to analyze the relationship with expression of these factors. Kaplan-Meier univariate analysis showed that the overexpression of cyclin D1 and epidermal growth factor receptor (EGFR) and late pathological stage after surgery indicated shorter RFT. Multivariate analysis showed that EGFR and the stage were independent predictors of RFT. Expression of EGFR and cyclin D1 and the pathological stage were included as combination risk factors for RFT analysis; more risk factors were correlated with shorter RFT. EGFR and cyclin D1 seemed to be indicators of the dynamics of tumor growth, and overexpression of those molecules may suggest rapid growth and poor prognosis.

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Biomarkers, Tumor; Cell Proliferation; Colorectal Neoplasms; Cyclin D1; ErbB Receptors; Female; Follow-Up Studies; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Prognosis; Survival Rate

It was reported that the receptor tyrosine kinase (RTK) family often highly expressed in several mucinous carcinomas. In the present study, we established a murine model of colorectal mucinous adenocardinoma (CRMAC) by treating C57 mice [both wild type (WT) and loss-of-function c-kit mutant type (Wads-/-)] with AOM+DSS for 37 weeks and found that c-kit, a member of RTK family, clearly enhanced the tumor cell proliferation by decreasing p53 and increasing cyclin D1 through AKT pathway. Significantly, c-kit strongly promoted tumor cell invasiveness by increasing ETV4, which induced MMP7 expression and epithelial-mesenchymal transition (EMT) via ERK pathway. In vitro up- or down-regulating c-kit activation in human colorectal cancer HCT-116 cells further consolidated these results. In conclusion, our data suggested that the c-kit signaling obviously promoted proliferation and invasion of CRMAC. Therefore, targeting the c-kit signaling and its downstream molecules might provide the potential strategies for treatment of patients suffering from CRMAC in the future.

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Animals; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Cyclin D1; Disease Models, Animal; Epithelial-Mesenchymal Transition; Extracellular Signal-Regulated MAP Kinases; Gene Expression Regulation, Neoplastic; Genotype; HCT116 Cells; Humans; Lentivirus; Matrix Metalloproteinase 7; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neoplasm Invasiveness; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-kit; Signal Transduction; Tumor Suppressor Protein p53

Breast cancer associated with BRCA1 and BRCA2 gene mutations differs from non-BRCA tumors in several respects. We determined whether there was any difference in CCND1 (11q13) and ZNF217 (20q13) gene amplification with respect to BRCA status. Of 40 breast cancer samples examined, 15 and 9 were from BRCA1 and BRCA2 mutation carriers, respectively, and 16 from patients without mutation. Fluorescence in situ hybridization showed that eight tumors exhibited CCND1 amplification (20%; 3 BRCA1, 3 BRCA2, 2 non-BRCA). ZNF217 amplification was observed in three of 38 cases (8%; 2 BRCA1, 1 non-BRCA). There was no significant difference in CCND1 and ZNF217 amplification between BRCA1, BRCA2 and non-BRCA tumors. CCND1 amplification was associated with decreased disease-free (P = 0.045) and overall survival (P = 0.015). BRCA1 tumors with CCND1 amplification were estrogen receptor negative, in contrast to CCND1 amplified BRCA2 and non-BRCA tumors, suggesting that concurrent CCND1 amplification and estrogen and progesterone receptor negativity may predict germline BRCA1 gene mutation. All ZNF217 amplified tumors were of the medullary histological type (P = 0.002). There was no statistical correlation between CCND1 and ZNF217 amplification and estrogen receptor, progesterone receptor, and ERBB2 expression and TNM classification. CCND1 amplification did not correlate with EGFR expression.

Topics: Adenocarcinoma, Mucinous; Adult; Apoptosis Regulatory Proteins; BRCA1 Protein; BRCA2 Protein; Breast Neoplasms; Carcinoma, Ductal, Breast; Carcinoma, Lobular; Cyclin D1; ErbB Receptors; Female; Gene Amplification; Genetic Predisposition to Disease; Germ-Line Mutation; Humans; Immunoenzyme Techniques; In Situ Hybridization, Fluorescence; Middle Aged; Prognosis; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Trans-Activators; Young Adult

p55PIK is one of the regulatory subunits of phosphoinositide-3 kinase (PI3K). The unique 24 amino acids at N-terminal of p55PIK can bind Rb, and their ectopic expression may inhibit cell cycle progression. This study was to observe the effects of ectopic expression of the 24 amino acids at N-terminal of p55PIK (N24p55PIK) on cell proliferation and tumor growth of gastric cancer, and explore possible mechanism.. Plasmid pEGFPN24 was transfected into gastric cancer cell line MGC803 (MGC803/GFP-N24); pEGFPC1 was transfected into MGC803 cells as control (MGC803/pEGFPC1). Transient expression of GFP-N24 fusion protein was confirmed by Western blot. The growth of cell clones was determined by MTT assay. Effect of N24p55PIK overexpression on cell clonogenic ability was detected by colony formation assay. Tumorigenic capacity of MGC803/GFR-N24 cells was tested by tumorigenicity assay in nude mice. Influence of N24p55PIK on the expression of cell cycle protein Cyclin D1 was analyzed by Western blot.. N24p55PIK was efficiently expressed in MGC803 cells, but the level of GFP-N24 fusion protein in MGC803/GFP-N24 cells was much lower than that of GFP in MGC803/pEGFPC1 cells. Compared with MGC803/pEGFPC1 cells, the growth of MGC803/GFP-N24 cells was suppressed and the cell doubling time was prolonged. The volume of MGC803/GFP-N24 cell colonies was smaller than that of MGC803/pEGFPC1 cell colonies. The tumorigenic capacity of MGC803 cells was decreased after transfection of pEGFPN24 in nude mice. The tumor weight and volume were (0.398+/-0.244) g and (408+/-268) mm(3) in MGC803/pEGFPN24 group, and were (0.763+/-0.193) g and (829+/-271) mm(3) in MGC803/pEGFPC1 group (P<0.05). The expression of Cyclin D1 was down-regulated in MGC803/GFP-N24 cells.. Ectopic expression of N24p55PIK might inhibit tumor cell growth both in vitro and in vivo through decreasing the expression of Cyclin D1. The N24 peptide, derived from PI3K regulatory subunit p55PIK, may be a potential drug in antitumor treatment.

Topics: Adenocarcinoma, Mucinous; Animals; Cell Line, Tumor; Cell Proliferation; Cyclin D1; Down-Regulation; Humans; Mice; Mice, Nude; Neoplasm Transplantation; Phosphatidylinositol 3-Kinases; Plasmids; Recombinant Fusion Proteins; Stomach Neoplasms; Transfection

Abnormality of cell cycle regulation is an important cause of cell over-proliferation and oncogenesis. But the relationship between cell cycle regulators and gastric carcinoma is uncertain. This study was to investigate the expression and significance of cell cycle regulators, including P16(INK4), Cyclin D1, P21(WAF1), and P53, in gastric carcinoma.. The expressions of P16(INK4), Cyclin D1, P21(WAF1), and P53 in 53 specimens of gastric carcinoma were observed by SP immunohistochemistry. Multivariate Cox regression was used to analyze factors affecting prognosis.. Positive rate of P53 in gastric carcinoma was higher than that in adjacent tissues (60.4% vs. 0, P < 0.01); those in well, and poorly differentiated adenocarcinoma were significantly higher than that in mucoid carcinoma (65.4%, and 68.2% vs. 0, P < 0.01). Over-expression rate of Cyclin D1 in gastric carcinoma was higher than that in adjacent tissues (69.8% vs. 5.7%, P < 0.01). Positive rate of P16(INK4) in gastric carcinoma was lower than that in adjacent tissues (60.3% vs. 88.6%, P < 0.05). Positive rate of P21(WAF1) in gastric carcinoma was lower than that in adjacent tissues (26.4% vs. 56.6%, P < 0.01). Positive rate of P16(INK4) was significantly related with the depth of tumor invasion (P < 0.05), and lymph node metastasis (P < 0.01). Multivariate Cox regression analysis indicated that lymph node metastasis and the expression of P16(INK4) were independent prognostic factors of gastric carcinoma.. Down-regulation of P16(INK4) and P21(WAF1), and over-expression of Cyclin D1 and P53 are significantly related to genesis and progression of gastric carcinoma. Down-regulation of P16(INK4) may be correlated to infiltration, metastasis, and prognosis of gastric carcinoma.

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Adult; Aged; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p16; Cyclin-Dependent Kinase Inhibitor p21; Female; Follow-Up Studies; Gastric Mucosa; Humans; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Invasiveness; Neoplasm Staging; Prognosis; Proportional Hazards Models; Stomach Neoplasms; Tumor Suppressor Protein p53

Intraductal papillary mucinous tumours (IPMT) of the pancreas constitute a unique pathological entity with an overall incidence of associated invasive malignancy of 20%. The malignant potential of an individual IPMT cannot be accurately predicted. Preoperative estimation of the risk of associated invasive malignancy with IPMT would be of significant clinical benefit. As aberrations in cell cycle regulatory genes are associated with the progression of precursor pancreatic ductal lesions to invasive adenocarcinoma, we examined expression of key cell cycle regulatory genes in the cyclin D1/retinoblastoma pathway and the transforming growth factor beta/Smad4 signalling pathway in a cohort of patients with surgically resected IPMT.. Sections of formalin fixed paraffin embedded pancreatic tissue from a cohort of 18 patients with IPMT were examined using immunohistochemistry for protein expression of cell cycle regulatory genes p16(INK4A), p21(CIP1), p27(KIP1), cyclin D1, pRb, and p53, as well as the cell signalling molecule Smad4. A comparison of expression levels was made between adenoma/borderline IPMT (10 patients) and intraductal papillary mucinous carcinoma (IPMC) (eight patients, four of whom harboured invasive carcinoma). Statistical analysis was performed using the chi(2) and Fisher's exact tests.. Aberrant expression of the proteins examined increased in frequency from adenoma/borderline IPMT to IPMC. Specifically, there was a significantly greater incidence of loss of p16(INK4A) expression in IPMC: 8/8 lesions (100%) compared with 1/10 (10%) adenoma/borderline IPMT (p<0.001). Similarly, loss of Smad4 expression was associated with IPMC: 3/8 (38%) versus adenoma/borderline IPMT 0/10 (p<0.03). Loss of Smad4 expression within the IPMT was the best marker for the presence of invasive carcinoma (p<0.001).. These data indicate that loss of p16(INK4A) and Smad4 expression occur more frequently in IPMC alone, or with associated invasive carcinoma, compared with adenoma/borderline IPMT. Aberrant protein expression of these cell cycle regulatory genes in IPMT and pancreatic intraepithelial neoplasia in the current model of pancreatic cancer progression suggest similarities in their development and may also represent the subsequent risk of invasive carcinoma.

Topics: Adenocarcinoma, Mucinous; Aged; Aged, 80 and over; Carcinoma in Situ; Carcinoma, Pancreatic Ductal; Cell Cycle Proteins; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p16; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinase Inhibitor p27; Cyclins; DNA-Binding Proteins; Female; Humans; Immunohistochemistry; Male; Middle Aged; Pancreatic Neoplasms; Retinoblastoma Protein; Smad4 Protein; Trans-Activators; Tumor Cells, Cultured; Tumor Suppressor Protein p53; Tumor Suppressor Proteins