Abnormal glycosylation due to dysregulated glycosyltransferases and glycosidases is a key phenomenon of many malignancies, including colorectal cancer (CRC). In particular, increased ST6 Gal I (beta-galactoside alpha 2, 6 sialyltransferase) and subsequently elevated levels of cell-surface alpha 2, 6-linked sialic acids have been associated with metastasis and therapeutic failure in CRC. As many CRC patients experience metastasis to the liver or lung and fail to respond to curative therapies, intensive research efforts have sought to identify the molecular changes underlying CRC metastasis. ST6 Gal I has been shown to facilitate CRC metastasis, and we believe that additional investigations into the involvement of ST6 Gal I in CRC could facilitate the development of new diagnostic and therapeutic targets. This review summarizes how ST6 Gal I has been implicated in the altered expression of sialylated glycoproteins, which have been linked to CRC metastasis, radioresistance, and chemoresistance.
Antigens, CD/*metabolism ; Colorectal Neoplasms/*metabolism/pathology/*therapy ; Drug Resistance, Neoplasm ; Glycoproteins/*metabolism ; Humans ; Liver Neoplasms/secondary ; Lung Neoplasms/secondary ; Radiation Tolerance ; Receptor, Epidermal Growth Factor/metabolism ; Sialic Acids/*metabolism ; Sialyltransferases/*metabolism

The aim of the present study was to accurately evaluate the association of Sox2 expression with the survival of patients with digestive tract cancers. Relevant literatures were identified by comprehensively searching databases including the Pubmed, Embase, CBMdisc, and Wanfang (up to October 2014). A meta-analysis was performed to clarify the association between Sox2 expression and overall survival or clinicopathological parameters of patients with digestive tract cancers (esophageal, gastric, and colorectal cancers). The results showed a significant association between high Sox2 expression and poor overall survival in patients with digestive tract carcinomas (HR=1.55, 95% CI=1.04-2.31), especially for patients with esophageal cancer (HR=2.04, 95%CI=1.30-3.22), colorectal cancer (HR=1.40, 95% CI=1.04-1.89), and digestive tract adenocarcinoma (HR=1.80, 95% CI=1.12-2.89), for Europeans (HR=1.98, 95% CI=1.44-2.71) or patients who did not receive neoadjuvant treatment (HR=1.73, 95% CI=1.10-2.72). Furthermore, Sox2 over-expression was highly correlated with vascular invasion (OR=1.86, 95% CI=1.25-2.77) and poor differentiation (OR=1.88, 95% CI=1.14-3.08), especially in esophageal and colorectal cancers. In conclusion, Sox2 expression may serve as a novel prognostic factor for patients with digestive tract cancers. Over-expression of Sox2 that is correlated with vascular invasion and poor differentiation suggests poor outcomes of patients with digestive tract cancers.
Antineoplastic Agents ; therapeutic use ; Biomarkers, Tumor ; genetics ; metabolism ; Colorectal Neoplasms ; diagnosis ; drug therapy ; mortality ; pathology ; Esophageal Neoplasms ; diagnosis ; drug therapy ; mortality ; pathology ; Gastrointestinal Tract ; metabolism ; pathology ; Gene Expression ; Humans ; Neoadjuvant Therapy ; methods ; Neoplasm Grading ; Neoplasms, Vascular Tissue ; diagnosis ; drug therapy ; mortality ; secondary ; Prognosis ; SOXB1 Transcription Factors ; genetics ; metabolism ; Stomach Neoplasms ; diagnosis ; drug therapy ; mortality ; pathology ; Survival Analysis

OBJECTIVETo investigate the association between expressions of HSP70, HSP90 and efficacy of chemotherapy in colorectal cancer patients with unresectable liver metastasis.

METHODSData of 52 colorectal cancer cases, whose primary colorectal focuses were resected but hepatic metastatic tumors were unresectable, were reviewed retrospectively. All the patients underwent FOLFOX4 regimen well. Immunohistochemistry assay was applied to determine the expressions of HSP70 and HSP90 in primary focus tissues. The number and size of hepatic metastatic tumors pre- and post-chemotherapy were compared by CT scanning.

RESULTSPartial remission(PR) rate was 33.3% in cases with up-regulated expression of HSP70, while 64.5% in cases with down-regulated expression of HSP70, whose difference was significant. PR rate was 50% in cases with up-regulated expression of HSP90, and 53.1% in the others with down-regulated expression of HSP90, whose difference was not significant.

CONCLUSIONSFOLFOX4 regimen has advantages in cases with lower HSP70 expression over those with higher HSP70 expression. HSP90 expression level is not associated with the efficacy of FOLFOX4 regimen.

Adult ; Aged ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Colorectal Neoplasms ; drug therapy ; metabolism ; pathology ; Female ; HSP70 Heat-Shock Proteins ; metabolism ; HSP90 Heat-Shock Proteins ; metabolism ; Humans ; Liver Neoplasms ; drug therapy ; metabolism ; secondary ; Male ; Middle Aged ; Prognosis ; Treatment Outcome

OBJECTIVETo study lymph node micrometastases (LNMM), expression of nm23-H(1), MMP(9), TIMP(2) proteins, and their relationship and clinical significance in patients with stage Dukes B colorectal cancer.

METHODSThirty patients with stage Dukes B colorectal cancer were studied. LNMM in these patients was detected by immunohistochemical anti-cytokeratin 20 (CK20) staining. The expression of nm23-H(1), MMP(9) and TIMP(2) proteins in primary tumors was examined by Strept-avidin-biotin complex method. Clinical-pathological data and survival of each patient were recorded and analyzed.

RESULTS(1) The positive dyeing of CK20 was observed in 26.7% for cases and in 7.8% for lymph nodes of 30 patients with stage Dukes B colorectal cancer. (2) Different expression of nm23-H(1) and MMP(9) proteins in the patients between stage Dukes B and stage Dukes CD was observed (P < 0.05). The decreased nm23-H(1) expression, and/or the increased MMP(9) expression in primary stage Dukes B tumors were significantly associated with LNMM (P < 0.05). Sensitivity and specificity for detection of LNMM by using nm23-H(1) or MMP(9) were respectively 62.5% and 81.8% or 75.0% and 69.8%. If by combining nm23-H(1) with MMP(9), specificity for detection of LNMM became 90.9%. The expression of TIMP(2) protein was not related with stage Dukes and LNMM. (3) The percent of tumor recurrence and/or metastasis for the stage Dukes B patients with LNMM was significantly higher than that for the patients without LNMM (P < 0.05), but the survival percent for the patients with LNMM was significantly lower than that for the patients without LNMM. The outcome for the patients with nm23-H(1) (-) LNMM (+) or MMP(9) (+) LNMM (+) was significantly worse than that for patients with nm23-H(1) (+) LNMM (-) or MMP(9) (+) LNMM (-) (P < 0.05).

CONCLUSIONSLNMM is detected by immunohistochemical anti-CK20 staining. The expression of nm23-H(1) and MMP(9) in primary stage Dukes B tumors was significantly associated with LNMM. The outcome in the LNMM patients with nm23-H(1) (-) and/or MMP(9) (+) were worse. Combining examination of CK20 for lymph nodes with expression of nm23-H(1) and MMP(9) for primary tumors is of important clinical significance for staging of Dukes, selection of adjuvant treatment and evaluation of prognosis in patients with colorectal cancer.

Colorectal Neoplasms ; metabolism ; pathology ; therapy ; Humans ; Keratins ; metabolism ; Lymph Nodes ; pathology ; Lymphatic Metastasis ; Matrix Metalloproteinase 9 ; metabolism ; NM23 Nucleoside Diphosphate Kinases ; Neoplasm Staging ; Nucleoside-Diphosphate Kinase ; metabolism ; Prognosis ; Tissue Inhibitor of Metalloproteinases ; metabolism

OBJECTIVETo explore the effect of PI3K p85alpha gene silencing on the 5-fluorouracil (5-FU)-induced apoptosis of colorectal cancer cells.

METHODSThe PI3K p85alpha/RNAi transfected cells (PI3K p85alpha/RNAi-LoVo) were cultured in RPMI 1640 supplemented with 10% fetal calf serum and 500 microg/ml G418. The 50% inhibitory concentration (IC50) values of 5-FU (0.000625, 0.00125, 0.005, 0.01, 0.02, 0.04, 0.08, 0.16, 0.32 micromol/ml) were evaluated by MTT assay. Mitochondrial membrane potential was detected by JC-1 fluorescence, and Western blotting was used to analyze the expression of apoptotic proteins Bcl-6 and Bim.

RESULTSCompared with the untransfected LoVo cells, PI3K p85alpha/RNAi-LoVo showed obviously decreased IC(50) of 5-FU (P=0.000). The mitochondrial membrane potential of PI3K p85alpha/RNAi-LoVo cells was significantly lower than that of LoVo cells, suggesting that silencing PI3K p85alpha expression increased the sensitivity of LoVo cells to 5-FU. The expression of apoptotic protein Bcl-6 and Bim were significantly higher in PI3K p85alpha/RNAi-LoVo cells treated with 5-FU than LoVo cells (P=0.000).

CONCLUSIONPI3Kp85alpha gene silencing can significantly promote 5-FU-induced apoptosis of colorectal LoVo cells.

Apoptosis ; genetics ; Cell Line, Tumor ; Class Ia Phosphatidylinositol 3-Kinase ; genetics ; metabolism ; Colorectal Neoplasms ; genetics ; pathology ; Fluorouracil ; pharmacology ; Genetic Therapy ; methods ; Humans ; RNA Interference

Antibodies, Monoclonal ; therapeutic use ; Antibodies, Monoclonal, Humanized ; Antineoplastic Agents ; therapeutic use ; Cadherins ; genetics ; metabolism ; Carcinoma, Papillary ; pathology ; Cetuximab ; Colorectal Neoplasms ; drug therapy ; genetics ; pathology ; Consensus ; Dissent and Disputes ; Drug Delivery Systems ; Epithelial-Mesenchymal Transition ; Gastrointestinal Neoplasms ; classification ; pathology ; Genes, ras ; Humans ; Mutation ; Neoplasm Invasiveness ; Neoplastic Syndromes, Hereditary ; genetics ; metabolism ; pathology ; Neuroendocrine Tumors ; classification ; pathology ; Precancerous Conditions ; pathology ; Stomach Neoplasms ; genetics ; metabolism ; pathology

OBJECTIVETo investigate the expression of orotate phosphoribosyltransferase (OPRT) in colorectal carcinoma and analyze its correlations with the toxicities of chemotherapy.

METHODSThe expression of OPRT mRNA was detected using RT-PCR in colorectal carcinoma tissues and paired adjacent normal tissues from 58 patients receiving FOLFOX6 regimen chemotherapy. The toxicities of the chemotherapy were recorded, and the correlations between OPRT mRNA expression and the toxicities were analyzed.

RESULTSOPRT mRNA expression was significantly higher in the tumor tissues than in the corresponding normal tissues (P=0.001), but OPRT expression in the tumor tissues was not correlated with the toxicities of the chemotherapy (P>0.05). OPRT level in the normal tissues showed a significant positive correlation with the occurrence of diarrhea in these cases (P=0.013).

CONCLUSIONOPRT expression in colorectal carcinoma tissues is not correlated with the toxicities of 5-FU-based regimen, but OPRT expression in the normal tissues can help predict the toxicities associated with 5-FU.

Adult ; Aged ; Antimetabolites, Antineoplastic ; therapeutic use ; toxicity ; Colorectal Neoplasms ; drug therapy ; metabolism ; pathology ; Female ; Fluorouracil ; therapeutic use ; toxicity ; Humans ; Intestinal Mucosa ; metabolism ; pathology ; Male ; Middle Aged ; Orotate Phosphoribosyltransferase ; metabolism

Granulocyte colony-stimulating factor (G-CSF) is an essential regulator of neutrophil trafficking and is highly expressed in multiple tumors. Myeloid derived suppressor cells (MDSCs) promote neoplastic progression through multiple mechanisms by immune suppression. Despite the findings of G-CSF function in colon cancer progression, the precise mechanism of G-CSF on MDSCs regulation and its blockade effects on tumor growth remains a worthy area of investigation. In this study we observed an overexpression of G-CSF in a mouse colitis-associated cancer (CAC) model, which was consistent with the accumulation of MDSCs in mouse colon tissues. Further in vitro studies demonstrated that G-CSF could promote MDSCs survival and activation through signal transducer and activator of transcription 3 (STAT3) signaling pathway. Moreover, compared with isotype control, anti-G-CSF mAb treatment demonstrated reduced MDSC accumulation, which led to a marked decrease in neoplasm size and number in mice. Our results indicated that G-CSF is a critical regulating molecule in the migration, proliferation and function maintenance of MDSCs, which could be a potential therapeutic target for colitis-associated cancer.
Animals ; Carcinogenesis ; Colitis ; complications ; Colorectal Neoplasms ; complications ; drug therapy ; immunology ; metabolism ; Female ; Gene Expression Regulation, Neoplastic ; Granulocyte Colony-Stimulating Factor ; genetics ; metabolism ; Immunotherapy ; Mice ; Molecular Targeted Therapy ; Myeloid Cells ; immunology ; metabolism ; pathology

OBJECTIVETo study the effect of angiogenesis inhibitor YH-16 in combination with 5-FU on liver metastasis of colorectal cancer.

METHODSIn vitro, the inhibitory effects of YH-16 and 5-FU on the growth of vascular endothelial cells and colorectal cancer cells were examined by MTT assay. In vivo, colorectal cancer cells were transplanted into BALB/c mice, and the mice were divided into six groups randomly:control group, low-dose YH-16 group, middle-dose YH-16 group, high-dose YH-16 group, 5-FU group and combination group. The number of liver metastases, the size of primary tumor and the toxicity were examined after 2 weeks postoperatively. The expression of vascular endothelial growth factor (VEGF) in liver metastases was detected by immunohistochemistry, and tumor microvessel density (MVD) was measured by immunostaining with CD34 and factor VIII (monoclonal antibodies.

RESULTSIn vitro, YH-16 inhibited the growth of colon cancer cells and vascular endothelial cells, with the IC50 at (2.16+/-0.28) microg/ml and (0.64+/-0.10) microg/ml respectively. In vivo high-dose YH-16 and 5-FU had a remarkable inhibitory effect on liver metastasis, and the combination group showed significant enhancement on this effect (P< 0.05). The combination group and 5-FU group could inhibit the growth of primary tumor, but not found in YH-16 group. The toxicity of YH-16 was lower than that of 5-FU (P< 0.05), and the difference was not found in the toxicity between combination group and 5-FU group (P > 0.05). Expression of VEGF in liver metastases was clearly inhibited by YH-16 in combination with 5-FU or 5-FU alone compared to the control group, and MVD in middle-dose and high-dose YH-16 group, 5-FU group and combination group was lower than that in control group (P< 0.05).

CONCLUSIONSThe angiogenesis inhibitor YH-16 can inhibit liver metastasis of colorectal cancer through inhibiting the growth of vascular endothelial cells. YH-16 in combination with 5-FU has additive effect on inhibitory activity against liver metastasis.

Angiogenesis Inhibitors ; therapeutic use ; Animals ; Cell Line, Tumor ; Colorectal Neoplasms ; drug therapy ; pathology ; Drug Therapy, Combination ; Female ; Fluorouracil ; therapeutic use ; Liver Neoplasms ; prevention & control ; secondary ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Neoplasm Transplantation ; Vascular Endothelial Growth Factor A ; metabolism

OBJECTIVETo evaluate the effect of adenovirus-mediated CD/TK double suicide gene system on tumor growth and cytokine levels in the tumor microenvironment in mice bearing transplanted colorectal cancer.

METHODSCT26 cells were implanted subcutaneously into 30 Balb/c mice, which were subsequently randomized into the control (n=15) and experimental group (n=15). After the tumor formation, CD/TK double suicide gene system was administered for tumor treatment, and the changes in the tumor volume, tumor inhibition rate, and levels of cytokines in the tumor microenvironment were investigated.

RESULTSCD/TK double suicide gene system resulted in a significant inhibition of the tumor growth and significantly increased levels of such cytokines as IL-2, IL-10, TNFalpha and IFNgamma in the tumor microenvironment.

CONCLUSIONCD/TK double suicide gene system produces significant tumor inhibition effect and causes obvious cytokine changes in the tumor microenvironment in mice bearing transplanted colorectal cancer.

Adenoviridae ; genetics ; metabolism ; Animals ; Cell Proliferation ; Colorectal Neoplasms ; metabolism ; pathology ; therapy ; Cytokines ; metabolism ; Cytosine Deaminase ; genetics ; metabolism ; Female ; Genes, Transgenic, Suicide ; genetics ; Genetic Therapy ; methods ; Green Fluorescent Proteins ; genetics ; metabolism ; Interleukin-2 ; metabolism ; Male ; Mice ; Mice, Inbred BALB C ; Neoplasm Transplantation ; Random Allocation ; Recombinant Fusion Proteins ; genetics ; metabolism ; Thymidine Kinase ; genetics ; metabolism ; Tumor Necrosis Factor-alpha ; metabolism ; Vascular Endothelial Growth Factor A ; genetics ; metabolism