Semaphorin 4D and hypoxia-inducible factor-1α overexpression is related to prognosis in colorectal carcinoma

AIM:To investigate semaphorin 4D(Sema4D)and hypoxia-inducible factor-1α(HIF-1α)expression in colorectal carcinoma and evaluate their clinicopathological and prognostic significance.METHODS:Eighty-six curatively resected colorectal carcinoma patients at different stages of disease were randomly selected from the group of patients who underwent surgery,and none of them received preoperative radiochemotherapy.Normal proximal adjacent bowel tissue,which served as an internal control,was obtained from 52 randomly selected patients.Immunohistochemistry was performed to analyze the expression of Sema4D and the tumor angiogenesisrelated protein HIF-1αin normal colorectal tissues and colorectal carcinoma tissues.The relationships between the expression and clinical characters and prognosis were analyzed.RESULTS:HIF-1αand Sema4D were positively expressed in 58%and 60%of colorectal carcinoma tissues,respectively.Significantly lower expression levels were observed in normal mucosa(8%and 12%,respectively).HIF-1αand Sema4D expression was closely correlated with histological tumor type,tumornode-metastasis(TNM)stage,and lymphatic metastasis(P0.05),but not with age or tumor size(P0.05).HIF-1αand Sema4D protein expression was significantly correlated with prognosis of colorectal carcinoma,as determined by Spearman rank correlation analysis(r=0.567;P0.01).Multivariate Cox analysis revealed that only Sema4D expression played a significant role in predicting patient prognosis(P0.05).CONCLUSION:These findings suggest that HIF-1αand Sema4D expression correlates with histological tumor type,TNM stage,and lymphatic metastasis in colorectal carcinoma and that Sema4D is a prognostic indicator of colorectal carcinoma.     

Expression of NOS and HIF-1α in human colorectal carcinoma and implication in tumor angiogenesis

AIM: To study CD34, CD105, inducible nitric oxide synthase (iNOS), endogenous nitric oxide synthase (eNOS), and hypoxia-inducible factor 1 (HIF-1) alpha expression in human colorectal carcinomas. METHODS: The tissue microarrays (TMAs) were made up of 80 cases of colorectal carcinoma and 80 cases of non-neoplasm colorectal mucosa. The expression of CD34, CD105, NOS and HIF-1alpha was detected by immunohistochemistry (S-P). RESULTS: iNOS and HIF-1alpha expression in colorectal carcinoma was significantly higher than in non-neoplasm colorectal mucosa (c2 = 43.166, P < 0.01; c2 = 10.4278, P < 0.01); eNOS expression in colorectal carcinoma was significantly lower than in non-neoplasm colorectal mucosa (c2 = 11.354, P < 0.01). The expression of iNOS correlated with differentiation (c2 = 18.141, P < 0.01), invasive depth (c2 = 4.748, P < 0.01), and Micro vessel density (MVD) (t = 2.327, P < 0.05). The expression of HIF-1alpha was correlated with infiltrating depth (c2 = 4.397, P < 0.05), Dukeos staging (c2 = 4.255, P < 0.05), and MVD (t = 2.272, P < 0.05). No correlation was found in eNOS expression. CONCLUSION: Over-expression of iNOS and HIF-1alpha in colorectal carcinoma is correlated with the biological character MVD.     

Expression and clinical significance of CD73 and hypoxia-inducible factor-1α in gastric carcinoma

AIM: To investigate the expression of CD73 and hypoxia-inducible factor-1α (HIF-1α) in human gastric carcinoma, and explore their clinical significance and prognostic value. METHODS: CD73 and HIF-1α expressions were detected by immunohistochemistry in consecutive sections of tissue samples from 68 gastric carcinoma patients. The peritumor tissues 2 cm away from the tumor were obtained and served as controls. The presence of CD73 and HIF-1α was analyzed by immunohis-tochemistry using the Envision technique. RESULTS: CD73 and HIF-1α expressions in gastric carcinoma were significantly higher than those in gastric mucosal tissues as control (P < 0.001) and showed a close correlation (Spearman r = 0.390, P = 0.001). Overexpression of CD73 was positively correlated with differentiation of tumor (P = 0.000), histopathology (P = 0.041), depth of invasion (P < 0.001), nodal status (P = 0.003), metastasis (P = 0.013), and the American Joint Committee on Cancer (AJCC) stage (P < 0.001). High expression of HIF-1α was positively correlated with tumor diameter (P = 0.031), depth of invasion (P = 0.022), and AJCC stage (P = 0.035). The overall survival rate was low in the patients with high expression of CD73 (P < 0.001). Moreover, CD73+/HIF-1α+ patients had the worst prognosis (P < 0.001). CD73 expression was proven to be an independent predictor for patients with gastric carcinoma by both multivariate Cox regression analysis (P = 0.021) and receiver operating characteristic curves (P = 0.001).CONCLUSION: CD73 expression correlates closely with HIF-1α expression in gastric carcinoma. CD73 could be an independent prognostic indicator for gastric carcinoma.     

Role of TGF-β1, its receptor TGFβRII, and Smad proteins in the progression of colorectal cancer

Aim  

In the current study, we investigated the expression of TGF-β1, its receptor TGFβRII, and the signaling proteins Smad4 and Smad7 in colorectal cancer tissue in relation to infiltration with antigen-presenting cells and some clinical and pathologic parameters of disease progression in patients with colorectal cancer (CRC).     

Increased serum levels of transforming growth factor-α in patients with colorectal cancer

PURPOSE: This study was conducted to investigate the serum levels of transforming growth factor- in patients with colorectal cancer and to investigate the clinical significance of these levels in association with tumor stage and histologic differentiation. Also, serum levels of transforming growth factor- were measured after curative surgical resection. METHODS: Serum levels of transforming growth factor- were measured in 42 consecutive patients with colorectal cancer before surgery, in 21 patients after surgical resection (part of the 42 preoperative patients), and in 20 healthy volunteers. We used TGF- Assay. RESULTS: Serum levels of transforming growth factor- in patients with colorectal cancer were significantly higher than in the healthy control group (P=0.001). Significant elevations in serum levels of transforming growth factor- were found in 50 percent (21/42) of patients with colorectal cancer when the mean + 2 standard deviations (80.4 pg/ml) of the control group were used as the upper limit of the normal range. Serum levels of transforming growth factor- tended to decrease with increasing tumor size (n=31;r=–0.52;P=0.002). Serum levels of transforming growth factor- before surgery (89.7±44.4 pg/ml; n=21) significantly decreased to 60.3±19.8 pg/ml after surgical resections of tumors (P=0.017). Serum levels of transforming growth factor- completely decreased to the same serum levels of the control group after surgical resections in all patients who had serum levels of transforming growth factor- greater than mean + 2 standard deviations (80.4 pg/ml) of the control group preoperatively (n=11;P=0.002). CONCLUSIONS: Levels of preoperative transforming growth factor- in patients with colorectal cancer appeared to be higher than levels measured in control subjects. Serum levels of transforming growth factor- before surgery significantly decreased after surgical resections of tumors. Additional studies are warranted to determine if serum levels of transforming growth factor- may be useful as a potential biomarker in the management of patients with colorectal cancer.Supported by a grant from Ewha Womans University Mokdong Hospital, Seoul, Korea.Read at the meeting of The American Society of Colon and Rectal Surgeons, Philadelphia, Pennsylvania, June 22 to 26, 1997.     

Expression of NOS and HIF-1αin human colorectal carcinoma and implication in tumor angiogenesis

AIM: To study CD34, CD105, inducible nitric oxide synthase (iNOS), endogenous nitric oxide synthase (eNOS), and hypoxia-inducible factor 1 (HIF-1)αexpression in human colorectal carcinomas. METHODS: The tissue microarrays (TMAs) were made up of 80 cases of colorectal carcinoma and 80 cases of non-neoplasm colorectal mucosa. The expression of CD34, CD105, NOS and HIF-1αwas detected by immunohistochemistry (S-P). RESULTS: iNOS and HIF-1αexpression in colorectal carcinoma was significantly higher than in non-neoplasm colorectal mucosa (X2 = 43.166, P < 0.01; X2 = 10.4278, P < 0.01); eNOS expression in colorectal carcinoma was significantly lower than in non-neoplasm colorectal mucosa (X2 = 11.354, P < 0.01). The expression of iNOS correlated with differentiation (X2 = 18.141, P < 0.01), invasive depth (X2 = 4.748, P < 0.01), and Micro vessel density (MVD) (t = 2.327, P < 0.05). The expression of HIF-1αwas correlated with infiltrating depth (X2 = 4.397, P < 0.05), Duke's staging (X2= 4.255, P < 0.05), and MVD (t = 2.272, P < 0.05). No correlation was found in eNOS expression. CONCLUSION: Over-expression of iNOS and HIF-1αin colorectal carcinoma is correlated with the biological character MVD.     

Loss of heterozygosity on hromosome 1 in sporadic colorectal carcinoma

AIM: Loss of heterozygosity (LOH) on tumor suppressorgenes is believed to play a key role in carcinogenesis ofcolorectal cancer.When it occurs at a tumor suppressorgene locus with abnormal allele,neoplastic transformationhappens.In this study,we analyzed the LOH at 21 loci onchromosome 1 in sporadic colorectal cancer to identifyadditional loci involved in colorectal tumorigenesis.METHODS: Twenty-one polymorphic micro-satellite DNAmarkers were analyzed with PCR both in 83 cases ofcolorectal cancer and in normal tissues.PCR products wereeletrophoresed on an ABI 377 DNA sequencer.Genescan3.1 and Genotype 2.1 software were used for LOH scanningand analysis.χ~2 test was used to compare LOH frequencywith clinicopathological data.P<0.05 was considered asstatistically significant.RESULTS: The average LOH frequency of chromosome 1,short arm and long arm was 19.83%,18.00% and 21.66%,respectively.The 2 highest LOH loci with a frequency of36.54% and 32.50% were identified on DIS468 (1p36.33-p36.31) and DIS413 (1q31.3),respectively.On DIS2726locus,LOH frequency of rectal cancer was 28.57% (6/21),which was higher than that of colon cancer (0.00%,0/33)(P=0.002),suggesting that the mechanism of carcinogenisiswas different in both groups.CONCLUSION: Putative tumor suppressor genes onchromosome 1 may relate to sporadic colorectal carcinomas.Tumor-suppressor-genes might locate on 1p36.33-36.31and/or 1q31.3.     

Expression of transforming growth factor-α and hepatitis B surface antigen in human hepatocellular carcinoma tissues and its significance

AIM:To evaluate the expression of transforming growthfactor-alpha (TGF-α) and hepatitis B surface antigen (HBsAg)in human hepatocellular carcinoma (HCC) tissues and itssignificance.METHODS:Seventy specimens of HCC tissues weredetected by immunohistochemical method.Five specimensof normal human liver tissues were used as control.RESULTS:The TGF-α positive expression rates in HCCand its surrounding tissues were 74.3%(52/70) and88.1%(52/59),respectively.TGF-α positive granules weremainly in the cytoplasm and fewer existed on thekaryotheca.The TGF-α positive expressing rate in welldifferentiated HCC was significantly higher than that inmoderately and poorly differentiated HCC (P<0.05).TheTGF-α positive expression also was observed in intrahepaticbile ducts (part of those were hyperplastic ducts).TheHBsAg positive expression rates in HCC and its surroundingtissues were 21.4%(15/70) and 79.7%(47/59),respectively.HBsAg positive granules were in the cytoplasm,inclusionand on the karyotheca.There was a prominent positivecorrelation between TGF-a and HBsAg expression in HCCsurrounding tissues (P<0.05,γ=0.34).TGF-α was usuallyexisted with HBsAg in regenerated and/or dysplastic livercells.In the five normal liver tissues,TGF-α and HBsAgwere not detectable in hepatocytes and bile ducts.CONCLUSION:Hepatitis B virus infection is closely relatedwith hepatocarcinogenesis.The overexpression of TGF-αin the liver seems to be associated with the regenerationof hepatocytes injured by HBsAg.The continued expressionof TGF-α might lead to dysplasia of liver cells anddevelopment of HCC.Furthermore,TGF-α might play arole in morphogenesis and regeneration of intrahepaticbile ducts.     

Quantitative analysis of hepatic hypoxia-inducible factor-1α and its abnormal gene expression during the formation of hepatocellular carcinoma

BACKGROUND:Hepatic hypoxia-inducible factor-1(HIF-1) is activated in the progression of hepatocellular carcinoma (HCC).This study aimed to investigate the dynamic alterations of HIF-1αand its gene expression so as to explore the relationship between HIF-1αexpression and hepatocarcinogenesis at the early stage of HCC. METHODS:A hepatoma model was made with 2-fluorenyl- acetamide(2-FAA)in male Sprague-Dawley rats.Morphological changes of rat hepatocytes were assessed pathologically (HE staining).The dynamic e...     

Expression of HSP90 and HIF-1α in human colorectal cancer tissue and its significance

Objective:To investigate the expression of HSP90 and HIF-1αin human colorectal cancer tissue,the influence of HSP90 and HIF-1αon human colorectal cancer biological behavior and their related factors.Methods:The expression of HSP90 and HIF-1 a protein in human colorectal cancer as well as normal tissue were detected by imnmnohistochemical method.Results:The positive expression rates of HSP90 and HIF-1αprotein in normal human colorectal tissue as well as colorectal cancer tissue were 30%vs.63.0%,15.0%vs.71.7%,respectively.There were significant difference(P=0.035 and P=0.005 respectively).The expression of HSP90 was significantly correlated with the differentiation,Dukes stages and lymph node metastasis(P0.05),while the expression of HIF-1 a was significantly correlated with the Dukes stages and lymph node metastasis(P0.05).Association analysis showed that the expression of HSF90 protein was significantly correlated with that of HIF-1αprotein(P0.01).Conclusions:The expression of HSP90 and HIF—1αprotein may be related to the development,metastasis and invasion of human colorectal cancer,and their synergistic effects may participate in the development of the colorectal carcinoma.