Oestrogen receptor beta expression and depth of myometrial invasion in human endometrial cancer

We assessed the relative expression of oestrogen receptor (ER)alpha and oestrogen receptor (ER)beta mRNAs in 36 human endometrial cancers using a multiplex polymerase chain reaction (PCR). To determine whether or not the expression of ER subtypes in endometrial cancers is associated with clinicopathological parameters, we examined correlations between ER subtypes and age, tumour grade and depth of myometrial invasion. Using multiple regression analysis, myometrial invasion showed a significant correlation with ER-beta: ER-alpha ratio (r = 0.54, P = 0.0007). The ER-beta:ER-alpha ratio was high in advanced invasive carcinoma. Western blotting analysis showed that ER-beta proteins were highly expressed in comparison with ER-alpha proteins in endometrial cancer with severe myometrial invasion. Our results suggest that ER-beta is important in the progression of myometrial invasion.     

Loss of tumoral expression of soluble IL-6 receptor is associated with disease progression in colorectal cancer

Background:

Interleukin-6 (IL-6) binds both the membrane and soluble forms of the IL-6 receptor (sIL-6R), which induces a complex with gp130, and proliferation of tumour cells. The aim of this study is to clarify the relationship between tumoral sIL-6R expression and disease progression in colorectal cancer patients.

Methods:

We measured tissue concentrations of sIL-6R in tumour and normal mucosa from 161 colorectal cancer patients undergoing surgery, and in supernatants from colon cancer cell lines. The expression of IL-6, IL-6R and gp130 was evaluated by immunohistochemical analysis.

Results:

Loss of tumour expression of sIL-6R as defined by sIL-6R Ca/N ratio <1.0 was significantly associated with factors reflecting disease progression, and was an independent prognostic factor not only in all the patients in this study, but also in the patients with curative intent. Colon cancer cell lines produced sIL-6R in vitro, and the production of sIL-6R in cancer cell lines was stimulated by cytokine stimulation. Immunohistochemistry revealed that loss of tumour expression of sIL-6R was significantly inversely correlated with intense IL-6 expression in the cytoplasm of cancer cells. In addition, tumoral IL-1β expression was significantly correlated with sIL-6R expression.

Conclusion:

Loss of tumour expression of sIL-6R is associated with colorectal cancer disease progression.     

FAK alternative splice mRNA variants expression pattern in colorectal cancer

The Focal adhesion kinase (FAK) is a ubiquitous cytoplasmic tyrosine-kinase promoting tumor progression and metastasis processes by acting in cancer cells and their tumor microenvironment partners. FAK overexpression in primary colon tumors and their metastasis is associated to poor colorectal cancer (CRC) patients’ outcome. Eight FAK mRNA alternative splice variants have been described and contribute to additional level of FAK activity regulation, some of them corresponding to overactivated FAK isoforms. To date, FAK mRNA alternative splice variants expression and implication in CRC processes remain unknown. Here, using different human CRC cells lines displaying differential invasive capacities in an in vivo murine model recapitulating the different steps of CRC development from primary tumors to liver and lung metastasis, we identified three out of the eight mRNA variants (namely FAK⁰, FAK²⁸ and FAK⁶) differentially expressed along the CRC process and the tumor sites. Our results highlight an association between FAK⁰ and FAK⁶ expressions and the metastatic potential of the most aggressive cell lines HT29 and HCT116, suggesting that FAK⁰ and FAK⁶ could represent aggressiveness markers in CRC. Our findings also suggest a more specific role for FAK²⁸ in the interactions between the tumors cells and their microenvironment. In conclusion, targeting FAK⁰, the common form of FAK, might not be a good strategy based on the numerous roles of this kinase in physiological processes. In contrast, FAK⁶ or FAK²⁸ splice variants, or their corresponding protein isoforms, may putatively represent future therapeutic target candidates in the development of CRC primary tumors and metastasis.     

Epidemiologic differences between women with colorectal cancer and women with ovarian cancer

BACKGROUND AND OBJECTIVES: The difference between the epidemiologic features of women with colorectal cancer and those with ovarian cancer has not been thoroughly studied. The aim of this study is to review the epidemiologic features of women with colorectal cancer and compare them with those of women with ovarian cancer. METHODS: The epidemiologic features of 705 women with colorectal cancer were compared with those of 503 women with primary epithelial ovarian cancer. Both groups included all women with the confirmed respective histologic diagnoses admitted to Roswell Park Cancer Institute between 1982 and 1996 who returned a voluntary self-administered epidemiologic questionnaire. RESULTS: Women with ovarian cancer were significantly younger, had higher education and income, had fewer children, and were more likely to have never been married and nulligravid than those with colorectal cancer. There was a significant difference in the contraceptive history between both groups among women > or = 45 years of age. More women with ovarian cancer had a family history of ovarian cancer and more women with colorectal cancer had a family history of colorectal cancer. CONCLUSIONS: The epidemiologic features of women with colorectal cancer are different from those with ovarian cancer. The difference between both groups might indicate difference in the environmental or genetic etiology of both cancers.     

Gene expression differences among different MSI statuses in colorectal cancer

Colorectal cancer is the third most common cancer in males and second in females. This disease can be caused by genetic and acquired/environmental factors. Microsatellite instability (MSI) is one of the major mechanisms in colorectal cancer. This mechanism is a specific condition of genetic hyper mutability that results from incompetent DNA mismatch repair. MSI has been applied to classify different colorectal cancer subtypes. However, the effects of MSI status on gene expression are largely unknown. In our study, we integrated the gene expression profile and MSI status of all CRC samples from the TCGA database, and then categorized the CRC samples into three subgroups, namely, MSI‐stable, MSI‐low, and MSI‐high, according to the MSI status. We applied a novel computational method based on machine learning and screened the genes specifically expressed for the different colorectal cancer subtypes. The results showed the distinct mechanisms of the different colorectal cancer subtypes with MSI status and provided the genes that may be the optimal standards to further classify the various molecular subtypes of colorectal cancer with distinct MSI status.     

FHIT基因在结直肠癌中的表达及其与细胞凋亡抑制的相关性

Objective： To investigate the expression of fragile histidine triad （FHIT） protein in normal colorectal tissue, colorectal adenoma and colorectal cancer （CRC）, and to study the relationships between the expression of FHIT protein and the clinical pathology, the apoptosis-associated protein （Bcl-2, Bax, Survivin）, apoptosis in colorectal cancer. Methods： Tissue microarray （TMA） and immunohistochemistry SP were used to detect the expression of FHIT gene, Bcl-2, Bax and Survivin in 16 cases of the normal colorectal tissue, 16 cases of colorectal adenoma and 80 cases of the colorectal cancer. TUNEL was used to detect the apoptosis index （Al） in 80 cases of the colorectal cancer. Results： （1） The positive rates of FHIT gene expression in normal colorectal tissue, colorectal adenoma and adenocancer were 93.75%, 68.75% and 46.25% respectively. There were no significant differences in the relationships between the FHIT gene expression and histological types, the gender as well as the age （P〉0.05）. There were significant relationships between FHIT gene expression and lymph node metastasis, histological grades, Duke＇s system as well as the 5-year survival rate after operation. （2） The positive rates of Bax, Bcl-2 and Survivin in colorectal adenocancer were 72.50%, 51.25%, 77.50% respectively. The expression of FHIT gene was positively correlated with that of Bcl-2, Bax and Survivin. （3） The mean AI in FHIT negative tumors was significantly lower than that in FHIT positive tumors （P〈0.01）. Conclusion： FHIT gene may play a role in the oncogenesis and progression of colorectal cancer. The abnormal regulation of apoptosis may play an important role in the pathogenesis of colorectal cancer.     

NEAT expression is associated with tumor recurrence and unfavorable prognosis in colorectal cancer

Long noncoding RNAs (lncRNAs) have recently been identified to be involved in various diseases including cancer. NEAT1 is a recently identified lncRNA with its function largely unknown in human malignancy. In the present study, we investigated NEAT1 expression in 239 cases of clinical colorectal cancer specimens and matched normal tissues. Statistical methods were utilized to analyze the association of NEAT1 with clinical features, disease-free and overall survival of patients. Results showed that NEAT1 expression in colorectal cancer was up-regulated in 72.0% (172/239) cases compared with corresponding normal counterparts, and related to tumor differentiation, invasion, metastasis and TNM stage. Kaplan-Meier analysis proved that NEAT1 was associated with both disease-free survival and overall survival of patients with colorectal cancer that patients with high NEAT1 expression tend to have unfavorable outcome. Moreover, cox’s proportional hazards analysis showed that high NEAT1 expression was an independent prognostic marker of poor outcome. These results provided the first evidence that the expression of NEAT1 in colorectal cancer may play an oncogenic role in colorectal cancer differentiation, invasion and metastasis. It also proved that NEAT1 may serve as an indicator of tumor recurrence and prognosis of colorectal cancer.     

Low expression of gamma-glutamyl hydrolase mRNA in primary colorectal cancer with the CpG island methylator phenotype

The CpG island methylator phenotype (CIMP+) in colorectal cancer (CRC) is defined as concomitant and frequent hypermethylation of CpG islands within gene promoter regions. We previously demonstrated that CIMP+ was associated with elevated concentrations of folate intermediates in tumour tissues. In the present study, we investigated whether CIMP+ was associated with a specific mRNA expression pattern for folate- and nucleotide-metabolising enzymes. An exploratory study was conducted on 114 CRC samples from Australia. mRNA levels for 17 genes involved in folate and nucleotide metabolism were measured by real-time RT-PCR. CIMP+ was determined by real-time methylation-specific PCR and compared to mRNA expression. Candidate genes showing association with CIMP+ were further investigated in a replication cohort of 150 CRC samples from Japan. In the exploratory study, low expression of gamma-glutamyl hydrolase (GGH) was strongly associated with CIMP+ and CIMP+-related clinicopathological and molecular features. Trends for inverse association between GGH expression and the concentration of folate intermediates were also observed. Analysis of the replication cohort confirmed that GGH expression was significantly lower in CIMP+ CRC. Promoter hypermethylation of GGH was observed in only 5.6% (1 out of 18) CIMP+ tumours and could not account for the low expression level of this gene. CIMP+ CRC is associated with low expression of GGH, suggesting involvement of the folate pathway in the development and/or progression of this phenotype. Further studies of folate metabolism in CIMP+ CRC may help to elucidate the aetiology of these tumours and to predict their response to anti-folates and 5-fluorouracil/leucovorin.     

Non-genomic action of resveratrol on androgen and oestrogen receptors in prostate cancer: modulation of the phosphoinositide 3-kinase pathway

Prostate cancer represents a major concern in human oncology and the phytoalexin resveratrol (RES) inhibits growth and proliferation of prostate cancer cells through the induction of apoptosis. In addition, previous data indicate that in oestrogen-responsive human breast cancer cells, RES induces apoptosis by inhibition of the phosphoinositide-3-kinase (PI3K) pathway. Here, using androgen receptor (AR)-positive LNCaP and oestrogen receptor alpha (ERalpha)-expressing PC-3 prostate tumour cells, we have analysed whether the antiproliferative activity of RES takes place by inhibition of the AR- or ERalpha-dependent PI3K pathway. Although RES treatment (up to 150 microM) decreased AR and ERalpha protein levels, it did not affect AR and ERalpha interaction with p85-PI3K. Immunoprecipitation and kinase assays showed that RES inhibited AR- and ERalpha-dependent PI3K activities in LNCaP and PC-3, respectively. Consistently, lower PI3K activities correlated with decreased phosphorylation of downstream targets protein kinase B/AKT (PKB/AKT) and glycogen synthase kinase-3 (GSK-3). GSK-3 dephosphorylation could be responsible for the decreased cyclin D1 levels observed in both cell lines. Importantly, RES markedly decreased PKB/AKT phosphorylation in primary cultures from human prostate tumours, suggesting that the mechanism proposed here could take place in vivo. Thus, RES could have antitumoral activity in androgen-sensitive and androgen-non-sensitive human prostate tumours by inhibiting survival pathways such as that mediated by PI3K.     

Factors that contribute to faecal cyclooxygenase-2 mRNA expression in subjects with colorectal cancer

Background:

We previously reported that a faecal cyclooxygenase-2 (COX-2) mRNA assay was useful for identifying colorectal cancer (CRC). This study sought to investigate the factors that contribute to faecal COX-2 mRNA expression in subjects with CRC.

Methods:

The study cohort comprised 78 patients with CRC and 36 control subjects. The expressions of COX-2, β-2-microglobulin (B2M), carcinoembryonic antigen (CEA), E-cadherin (E-cad), and CD45 mRNA in faeces and COX-2 mRNA expression in tissue were determined by quantitative real-time RT–PCR.

Results:

The level of faecal expression of COX-2 mRNA in CRC was significantly higher than that in controls. A significant correlation was found between faecal COX-2 mRNA expression and faecal B2M, CEA, E-cad, or CD45 mRNAs, markers of exfoliated total cells, colonocytes, and leukocytes, respectively. A significant correlation was found between the expression of COX-2 mRNA in faeces and tumour surface area, COX-2 mRNA expression in primary tumour. There was no difference in faecal COX-2 mRNA expression between proximal CRC and distal CRC.

Conclusion:

COX-2 mRNA expression in faeces seems to originate from tumour lesion and to be affected by factors such as the number of exfoliated cells, exfoliation of inflammatory cells, COX-2 mRNA expression in tumour, and tumour size.     

结直肠癌中 RhoGDI2的表达与肿瘤侵袭、转移及预后的关系

目的：探讨 RhoGDI2在结直肠癌中的表达与肿瘤侵袭、转移及预后的关系。方法：应用 Northern blot和 Western blot 检测具有不同侵袭、转移潜能的人结直肠癌细胞系（SW620、SW480）中 RhoGDI2 mRNA 及蛋白的表达。收集行手术切除并随访满5年的结直肠癌患者原发灶癌组织石蜡标本80例及相应的癌旁非癌组织、转移性淋巴结癌组织石蜡标本各20例。应用免疫组化法检测上述120例标本中 RhoGDI2蛋白的表达,分析其与临床病理特征及预后的关系。结果：SW620、SW480人结直肠癌细胞系中 RhoGDI2 mRNA 及蛋白的表达具有统计学差异（P <0.01）,前者表达均高于后者。结直肠癌相关组织中 RhoGDI2蛋白存在差异性表达（转移淋巴结癌组织>原发灶癌组织>癌旁非癌组织,P <0.01）。RhoGDI2蛋白在结直肠癌组织中的表达与肿瘤的浸润深度、淋巴结转移、远处转移、周围淋巴管浸润、周围神经浸润、TNM 分期显著相关（P <0.05）。RhoGDI2高表达的结直肠癌患者5年生存率显著低于低表达者（P <0.01）。高 RhoGDI2表达是结直肠癌的独立预后因素之一（P <0.05）。结论：RhoGDI2在结直肠癌中的高表达与肿瘤的侵袭、转移及预后不良密切相关,可能是一个有效的结直肠癌预后标志物。     

Cetuximab in metastatic colorectal cancer

Management of metastatic colorectal cancer has evolved in the last 10 years, with the availability of targeted therapies resulting in improvement in quality of life and overall survival. Cetuximab is a chimeric monoclonal antibody that binds to the EGF receptor, and the net effects are inhibition of tumor growth, invasion, angiogenesis and metastasis. Cetuximab binding to the EGF receptor is also known to augment the effects of chemotherapy and radiotherapy. Only tumors expressing wild-type KRAS respond to cetuximab and improvements in progression-free survival and overall survival are seen, whereas patients with mutant KRAS are considered to be resistant. Cetuximab is currently available worldwide for use as monotherapy or in combination with chemotherapy in first-, second- or third-line settings in metastatic colorectal cancer patients with wild-type KRAS.     

Role of netrin-1 and netrin-1 dependence receptors in colorectal cancers

Although cancer is a multifaceted disease, all cancer types share identical molecular and cellular mechanisms. These mechanisms involve a collection of alterations critical to the normal physiological functioning of cells, such as alterations of growth factor signalling pathways, angiogenesis, cell adhesion signals, DNA replication and apoptotic cell death. Many genes involved in the processes enumerated above are functionally inactive in tumour cells, designating them as putative 'tumour suppressor genes'. Back in the early 1990s, Vogelstein and colleagues suggested that a gene called DCC (for Deleted in Colorectal Cancer) could be a tumour suppressor gene because it was found to be deleted in more than 70% of colorectal cancers, as well as in many other cancers. During the last 15 years, controversial data have failed to firmly establish whether DCC is indeed a tumour suppressor gene. However, the recent observations that DCC triggers cell death and is a receptor for netrin-1, a molecule recently implicated in colorectal tumorigenesis, have prompted a renewal of interest in the role of DCC in tumorigenesis and suggest that the netrin-1/receptor pairs act as novel negative regulators of tumour development.     

Serum endostatin levels are elevated in colorectal cancer and correlate with invasion and systemic inflammatory markers

Background:

Endostatin, a fragment of collagen XVIII, is an endogenous angiogenesis inhibitor with anti-tumour functions. However, elevated circulating endostatin concentrations have been found in several human cancers including colorectal cancer (CRC).

Methods:

Serum endostatin levels were measured by enzyme-linked immunoassay from a series of 143 patients with CRC and from 84 controls, and correlated with detailed clinicopathological features of CRC, serum leukocyte differential count and C-reactive protein (CRP) levels.

Results:

Patients with CRC had higher serum endostatin levels than the controls (P=0.005), and high levels associated with age, tumour invasion through the muscularis propria and poor differentiation, but not with metastases. Endostatin levels showed a positive correlation with the markers of systemic inflammatory response and a negative correlation with the densities of tumour-infiltrating mast cells and dendritic cells. Collagen XVIII was expressed in tumour stroma most strikingly in blood vessels and capillaries, and in the muscle layer of the bowel wall.

Conclusions:

Elevated endostatin levels in CRC correlate with systemic inflammation and invasion through the muscularis propria. Increased endostatin level may be a result of invasion-related cleavage of collagen XVIII expressed in the bowel wall. The negative correlations between serum endostatin and intratumoural mast cells and immature dendritic cells may reflect angiogenesis inhibition by endostatin.     

High Pin1 expression is associated with tumor progression in colorectal cancer

BACKGROUND AND OBJECTIVES: Peptidyl prolyl cis-trans isomerase (Pin1) isomerizes only phosphorylated serine or threonine residues preceding proline in certain proteins and affects the protein function. Pin1 interacts with many signaling pathways, including Wnt signaling pathway that is crucial for colorectal tumorigenesis. Pin1 promotes cyclin D1 over-expression directly or through the stabilization of beta-catenin. Pin1 is over-expressed in some cancers such as prostate and breast cancers. This study aimed to determine whether Pin1 plays a role in colorectal tumorigenesis through the upregulation of beta-catenin and cyclin D1. METHODS: Immunohistochemical analyses were performed on 105 colorectal cancer tissue samples using anti-Pin1, anti-beta-catenin, and anti-cyclin D1 antibodies. We examined the relationships between Pin1 expression and clinicopathological factors, prognosis, and beta-catenin/cyclin D1 expression. RESULTS: High Pin1 expression was observed in 40 cases (38%) and positively correlated with histological type (P=0.0240), depth of invasion (P=0.0051), and staging (P=0.0027) of colorectal tumors. High Pin1 expression was also correlated with the over-expressions of both beta-catenin (P=0.0225) and cyclin D1 (P=0.0137). CONCLUSIONS: These results suggest that Pin1 plays an important role in colorectal tumorigenesis, presumably by increasing beta-catenin and cyclin D1 expressions.