Poorly-differentiated Cancer Research Articles

Adenocarcinoma in Ileal Pouch-Anal Anastomosis: The Cleveland Clinic Experience

Purpose: Total proctocolectomy with ileal pouch-anal anastomosis substantially reduces the risk for dysplasia and cancer associated with ulcerative colitis (UC). Cancer in ileal pouch-anal anastmosis (IPAA) patients with underlying UC is a rare, which has only been reported as single cases. Natural history of IPAA cancer in these patients and its risk factors have not been investigated and there is lack of consensus for endoscopic cancer surveillance for these patients. The aim of the study was to characterize the natural history and clinical features, and histology in a group of patients with cancer of IPAA. Methods: Pouch database of 2,750 cases was searched. All patients had a preoperative diagnosis of UC or indeterminate colitis. Patients with cancer from the pouch and/or anal transitional zone (ATZ) were identified. Clinical features of these patients were characterized. Results: Eight patients (0.29%) with adenocarcinoma of the pouch and/or ATZ were identified from the database. Average age at cancer diagnosis was 56.8 ± 12.5 (SD) years. The mean duration from IBD diagnosis to cancer and from ileostomy take-down after IPAA to cancer diagnosis was 22.8 and 8.7 years, respectively. Most [5/8(62.5%)] had regular pouch endoscopic-surveillance after IPAA. Six cases had ATZ cancers and 2 had cancers of the pouch. Conclusion: The risk for cancer of IPAA is small but real, which can occur in UC patients without pre-colectomy diagnosis of dysplasia or cancer. A disproportional high number of these patients had post-operative Crohn's disease of the pouch. The majority of the patients had histologic poorly-differentiated cancer. Mucosectomy does not necessarily prevent cancers of the ATZ or pouch.Table: Demographic and Clinical Features of the 8 Patients with Cancer of IPAA

Clinicopathological and molecular genetic analysis of HNPCC in China

To explore the clinicopathological and molecular genetic features of hereditary nonpolyposis colorectal cancer (HNPCC) in Chinese population. We collected 16 Chinese HNPCC families from Wenzhou, Zhejiang Province, China. Tumor tissues and peripheral white blood cells were studied using microdissection, microsatellite analysis, immunostaining of hMSH2 and hMLH1 proteins and direct DNA sequencing of hMSH2 and hMLH1 genes. (1) A total of 50 patients had CRC. Average age at diagnosis of the first CRC was 45.7 years; 40.9% and 28.7% of the CRCs were located proximal to the splenic flexure and in the rectum, respectively. Thirty-eight percent of the colorectal cancer patients had synchronous and metachronous CRC. 34.4% and 25% of the CRCs were poor differentiation cancer and mucinous adenocarcinoma, respectively. Fourteen extracoloni tumors were found, and the hepatic cancer was the most common tumor type. Twenty-one patients whose median survival time was 5.7 years died during 1-23 years. Twenty-nine patients have survived for 1-28 years, 58.6%, 41.4% and 24.1% patients have survived for more than 5, 10 and 15 years, respectively; (2) All nine tumor-tissues showed microsatellite instability (MSI) at more than two loci. Four tumor-tissues lost hMSH2 protein expression and one lost hMLH1 protein expression. Three pathological germline mutations were identified from five genetically analyzed families; two of three mutations had not been reported previously as they were a transition from C to A in exon 14 (codon 743) of hMSH2 and a TTC deletion in exon 14 (codon 530) of hMLH1. Chinese HNPCC have specific clinicopathological features, such as early onset, propensity to involve the proximal colon, and high frequency of multiple CRCs, liver cancer more frequent than endometrial cancer. Chinese HNPCC showed relatively frequent germline mutation of mismatch repair (MMR) genes that correlated closely with high-level MSI and loss of expression of MMR genes protein.

Effect of STAT3 phosphorylation and p53 expression on human epidermal non melanoma cutaneous tumors

To investigate the effect of stat3 phosphorylation and p53 expression on human epidermal non-melanoma cutaneous tumours. Immunohistochemistry technique was employed to measure the expression of p-stat3 and p53 protein in skin tissue from 30 cases of skin squamous cell carcinoma (SCC), 20 cases of basal cell carcinoma (BCC), 20 cases of seborrhoeic keratosis (SK) and 20 normal subjects. (1) p-stat3 protein was abnormally increased in SCC and BCC as compared with normal skin and SK. Expression of p-stat3 in SCC was also significantly higher than that in BCC. (2) Expression of p-stat3 was higher in poorly-differentiated cancers than that in well-differentiated cancers in SCC. The positive rate of p-stat3 expression was correlated with the depth of tumor invasion, but not with tumor size. (3) There was no p53 protein expression on normal skin and SK, it was significantly upregulated in SCC and BCC. In SCC, the intensity of p53 expression was associated with tumor differentiation. There was no correlation between the positive rate of p53 expression and the depth of tumor invasion, whereas the positive rate of p53 expression was correlated with the sun-exposure area. (4) There existed positive correlation between the expression intensity of p-stat3 and p53 in SCC (r=0.641, P<0.05). (1) The overexpression of p-stat3 may play an important role in the development of epidermal tumors. (2) The abnormal activation of stat3 may be related to metastatic potentials in SCC. (3) Both p53 gene and stat3 may contribute to the pathogenesis of skin SCC.

25-Hydroxy-Vitamin D Metabolism in Human Colon Cancer Cells during Tumor Progression

RT-PCR analysis showed elevated expression of 25-hydroxyvitamin D-1α-hydroxylase (1α-OHase) and of 25-hydroxyvitamin D-24-hydroxylase (24-OHase) in well differentiated human colon carcinomas in comparison to normal mucosa. Further tumor progression is associated with a rise in 1α-OHase but with no significant change in 24-OHase mRNA expression. Accordingly, HPLC analysis of 25-hydroxy-vitamin D3 metabolism in freshly isolated tumor cells indicated that well to moderately differentiated colon cancers in situ are able to produce 1α,25-dihydroxyvitamin D3 (1α,25-(OH)2D3) and convert it through 24-OHase activity into side-chain modified metabolites, 1,24,25-(OH)3-D3 and 1,25-(OH)2- 24-oxo-D3. Likewise, 25-(OH)-D3 is metabolized into 24,25-(OH)2D3, 23,25-(OH)2D3, and 23,25-(OH)2-24-oxo-D3. Poorly-differentiated cancers expressed low levels of 1α-OHase mRNA, whereas 24-OHase was even over-expressed. RT-PCR and HPLC analysis of vitamin D metabolism in primary culture cell clones strongly suggested that the extent of endogenously produced 1α,25-(OH)2-D3 was inversely related to 24-OHase activity, which could thus limit the antimitotic efficacy of 1α,25-(OH)2-D3 particularly at late stages of colon cancer progression.

Use of systematic biopsy results to predict pathologic stage in patients with clinically localized prostate cancer: a preliminary report.

The purpose of this study was to determine the ability of clinical tests to predict advanced pathologic stage (seminal vesicle invasion, pT3c, or pelvic lymph node metastases, pN+). T stage, PSA, PSA density, and pathologic features in systematic biopsy specimens were correlated with pathologic stage in 190 consecutive patients with clinically localized (T1-3) prostate cancer detected by systematic needle biopsies and treated with radical prostatectomies. Thirty-three patients (17%) had an advanced pathologic stage cancer (pT3c or pN+). In logistic regression analysis, the total length of cancer in all biopsy cores (P < 0.0005), the percent of poorly-differentiated cancer in each specimen (P< 0.021), and serum PSA (P< 0.028) were the only significant predictors of advanced stage. A model was constructed to predict advanced stage: if the PSA was > or = 6 ng/mL and 4 or more biopsy cores were positive and the total length of cancer in all cores was > or = 20 mm and at least 10% of the cancer was poorly-differentiated, then 14 (93%) of 15 patients had an advanced pathologic stage cancer compared to 11% of the remaining 175 patients (P < 0.0005). The pathologic features of cancer in systematic needle biopsy specimens more accurately predicts which patients have advanced stage cancer than standard clinical tests alone.

Selective suppression of nuclear retinoic acid receptor beta gene expression in human pancreatic carcinomas

Retinoids restore normal cell growth and differentiation in malignant cells and are considered as potential therapeutic agents. Before using retinoids for the treatment of pancreatic cancer it is important to determine the expression of nuclear retinoid receptors, which mediate most actions of retinoids on gene expression in normal and malignant tissues. Digoxigenin-labeled antisense riboprobes of retinoic acid receptors (RARs) alpha, beta, and gamma, and retinoid X receptor (RXR) alpha were used for in situ hybridization to histological sections of-specimens from 24 human pancreatic carcinomas, 20 of which also contained adjacent normal tissue. All four receptors were detected in adjacent normal pancreatic tissue specimens and RAR-alpha, RAR-gamma, and RXR-alpha were also detected in all pancreatic carcinoma specimens. In contrast, RAR-beta mRNA transcripts were detected in only 67% of the malignant tissues and when expressed, the level of expression was significantly lower than that of the corresponding adjacent normal tissues. Decreased RAR-beta gene expression was especially noted in moderately- and poorly-differentiated cancers. These findings suggest that selective decrease or lass of RAR-beta gene expression in certain pancreatic carcinomas in vivo might be associated with the development or progression of pancreatic cancer.

5-FU DOSE-DEPENDENCY IN MTX/S-FU SEQUENTIAL THERAPY ASSESSED BY IN-VITRO ASSAY USING GASTRIC-CANCER CELL-LINES

The sequential administration of methotrexate (MTX) and 5-fluorouracil (5-FU) (MTX/5-FU therapy) on gastric cancers has shown higher response rates than standard chemotherapy. The response rate of these cancers, however, still showed from 18 to 48%. The purpose of this study was to determine the appropriate interval time and doses of MTX/5-FU therapy using a panel of 4 cell lines originated from the poorly-differentiated gastric cancers. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used as the chemosensitivity test. The sequential administration of MTX and 5-FU inhibited the growth of 2 cell lines more than 5-FU alone. In one cell line (GCIY), it inhibited the growth 6 times, and the longest interval time (6 h) was the most effective. In the other cell line (KATOIII), it inhibited growth 3 times, and the shortest interval time (O h) was the most effective. The growth inhibition in these cases did not depend on the dose of MTX (0.01 mu g/ml to 100 mu g/ml), but on the dose of 5-FU. In conclusion, 2 out of 4 cell lines showed a synergic effect between MTX and 5-FU. While the appropriate interval time between the two drugs varied between two cell lines, 5-FU dose was more critical than that of MTX. If 5-FU dose were to be increased in future trials with MTX, its efficacy might be higher. This model should also be good to screen other anti cancer drugs combined with MTX/5-FU therapy.

Chlorpheniramine inhibits the synthesis of ornithine decarboxylase and the proliferation of human breast cancer cell lines

Proliferation of both mouse and human breast cancer cells was inhibited by chlorpheniramine (CPA) in a dose-response manner. At the beginning of the exponential phase of growth (two days after seeding), 250 microM CPA was able to reduce cell proliferation by 75% (in Ehrlich cell cultures) and 30% (in MCF-7 cultures). The antiproliferative effect of CPA was also tested on a poorly-differentiated and hormone-insensitive human breast cancer cell line (MDA-MB231) and on a highly proliferative human colon cancer cell line (clone 3). CPA was cytotoxic for MDA-MB231 cells at concentrations higher than 50 microM, and it was also cytotoxic for the colon cancer cell clone 3 at 250 microM CPA. Nevertheless, colon cancer cells were slightly stimulated at CPA concentrations less than 100 microM. CPA reduced (by 50-70%) the ornithine decarboxylase induction occurring early after culture seeding of experimental mammary tumors (Ehrlich carcinoma cells) and human breast cancer cells (MCF-7). The presented data suggest that in addition to ODC inhibition, CPA presents other still unknown cytotoxic effects.

Immunocytochemical localization of fibroblast growth factor-1 (FGF-1) and FGF-2 in oral squamous cell carcinoma (SCC).

The localization of fibroblast growth factor-1 (FGF-1) and FGF-2 in human oral squamous cell carcinoma (SCC) was examined by immunohistochemical techniques using anti-FGF-1 and anti-FGF-2 monoclonal antibodies. Immunofluorescence staining of two oral SCC cell lines revealed that growing cancer cells were intensely positive for both FGF-1 and FGF-2, but confluent cells showed a faint immunostaining. In addition, two molecular mass species of FGF-1 (16 and 18 kDa) and one of FGF-2 (18 kDa) were identified by Western blot in cell extracts derived from growing SCC cells, but not from confluent SCC cells. The growing cell extracts significantly stimulated the proliferation of human umbilical vein endothelial cells. Immunoperoxidase staining of 13 oral SCC cases showed that both well-differentiated and poorly-differentiated cancer cells were positive for FGF-1 and FGF-2 with high frequency and intensity as compared to normal oral epithelium. These results indicate that SCC cells express high levels of endogenous FGF-1 and FGF-2, and suggest that these growth factors may contribute to cancer cell growth.

Deviant energetic metabolism of glycolytic cancer cells

The central glycolytic and oxidative pathways and the ATP-producing mechanisms differ in sane and malignant cells by their regulation and dynamics. Fast-growing, poorly-differentiated cancer cells characteristically show high aerobic glycolysis. In the same way, cholesterol biosynthesis, which occurs by normal pathways in tumors, is deficient in feed-back regulation and in sterol-transport mechanism. Other metabolic ways are deficient, as for example, intramitochondrial aldehyde catabolism, at the origin of a possible acetaldehyde toxicity, which can be circumvented by the synthesis of an unusual and neutral product for mammalian cells acetoin, through tumoral pyruvate dehydrogenase. If most of the glycolytic pyruvate is deviated to lactate production, little of the remaining carbons enter a truncated Krebs cycle where citrate is preferentially extruded to the cytosol where it feeds sterol synthesis. Glutamine is the major oxidizable substrate by tumor cells. Inside the mitochondrion, it is deaminated to glutamate through a phosphate-dependent glutaminase. Glutamate is then preferentially transminated to α-ketoglutarate that enters Krebs cycle. Glutamine may be completely oxidized through the abnormal Krebs cycle only if a way of forming acetyl CoA is present: cytosolic malate entering mitochondria is preferentially oxidized to pyruvate + CO 2 through an intramitochondrial NAD(P) + -malic enzyme, whereas intramitochondrial malate is preferentially oxidized to oxaloacetate through malate dehydrogenase, thus providing a high level of intramitochondrial substrate compartmentation. These and other regulatory aberrations in tumor cells appear to be reflections of a complex set of non-random phenotypic changes, initiated by expression of oncogenes.