Shao Chieh Lin

Suppression of dual-specificity phosphatase-2 by hypoxia increases chemoresistance and malignancy in human cancer cells.

Hypoxia inducible factor-1 (HIF-1) is the master transcriptional regulator of the cellular response to altered oxygen levels. HIF-1α protein is elevated in most solid tumors and contributes to poor disease outcome by promoting tumor progression, metastasis, and resistance to chemotherapy. To date, the relationship between HIF-1 and these processes, particularly chemoresistance, has remained largely unexplored. Here, we show that expression of the MAPK-specific phosphatase dual-specificity phosphatase-2 (DUSP2) is markedly reduced or completely absent in many human cancers and that its level of expression inversely correlates with that of HIF-1α and with cancer malignancy. Analysis of human cancer cell lines indicated that HIF-1α inhibited DUSP2 transcription, which resulted in prolonged phosphorylation of ERK and, hence, increased chemoresistance. Knockdown of DUSP2 increased drug resistance under normoxia, while forced expression of DUSP2 abolished hypoxia-induced chemoresistance. Further, reexpression of DUSP2 during cancer progression caused tumor regression and markedly increased drug sensitivity in mice xenografted with human tumor cell lines. Furthermore, a variety of genes involved in drug response, angiogenesis, cell survival, and apoptosis were found to be downregulated by DUSP2. Our results demonstrate that DUSP2 is a key downstream regulator of HIF-1-mediated tumor progression and chemoresistance. DUSP2 therefore may represent a novel drug target of particular relevance in tumors resistant to conventional chemotherapy.

Regulation of CD151 by Hypoxia Controls Cell Adhesion and Metastasis in Colorectal Cancer

Purpose: The first step of metastasis is the detachment of cancer cells from the surrounding matrix and neighboring cells; however, how cancer cells accomplish this process remains unclear. Thus, we aimed to investigate the underlying mechanism that controls the early event of metastasis. Experimental Design: One hundred and thirty-seven paired colorectal carcinoma and normal colon tissues were examined by immunohistochemical staining and Western blot for the expression of CD151, a member of the tetraspanin family that plays important roles in cell adhesion and motility. The effect of CD151 on cancer cell adhesion was investigated under normoxia and hypoxia conditions. Results: The level of CD151 was down-regulated in colon cancer compared with the paired normal counterparts. Expression of CD151 was negatively regulated by hypoxia inducible factor-1–dependent hypoxic stress. Suppression of CD151 by hypoxia caused the detachment of cancer cells from the surrounding matrix and neighboring cells whereas restoration of CD151 expression during reoxygenation facilitated the adhesion capacity. Clinical examination further showed that metastasized cancer cells expressed a greater level of CD151 compared with that of primary tumor. Conclusion: Regulation of CD151 by oxygen tension may play an important role in cancer metastasis by regulating the detachment from the primary site and homing in the secondary site.

The Prognostic Significance of RON and MET Receptor Coexpression in Patients with Colorectal Cancer

PurposeAlthough Recepteur d’Origine Nantais (RON), a member of the MET receptor tyrosine kinase family, is overexpressed and constitutively active in some primary tumors and tumor cell lines, its expression pattern and clinical significance in colorectal cancer are not well documented.MethodsBy using immunohistochemical staining, we examined RON and MET expression in 135 colorectal cancer specimens and investigated the association of the immunoreactivity of both receptors with colorectal cancer clinical parameters and prognosis.ResultsWe found moderate to strong expression in 99 cases (73 percent) for RON and 97 cases (72 percent) for MET. Univariate analysis showed that increased immunoreactivity of RON or MET was associated with shorter patient survival and that moderate to strong coexpression of both receptors was associated with a significantly worse prognosis. Multivariate Cox analysis showed that the risk of tumor recurrence for patients with high-RON/high-MET expression was approximately 11 times greater than for patients with low-RON/low-MET expression (P = 0.001). In addition, RON and MET expression levels were positively correlated (P ≤ 0.001; τ = 0.306).ConclusionsThe crosstalk between RON and MET in colorectal cancer seems important. Evaluating the expression patterns of RON and MET was predictive of clinical outcome for patients with colorectal cancer.

Hypoxia-regulated gene network in drug resistance and cancer progression

Hypoxia is a common phenomenon of solid tumors and contributes to aggressive phenotype and treatment failure. Hypoxia-inducible factor (HIF), a versatile transcription factor that regulates more than 5% of total human genes, not only plays important roles in controlling physiological processes, but is also a crucial mediator in hypoxia-induced tumor progression and chemoresistance. Overexpression of HIF-1α is detected in a wide spectrum of cancers via different kinds of mechanisms, including reduced oxygen concentration, loss-of-function of tumor suppressor gene, activating mutation of oncogenes, and hyperactivation of protein kinase signaling pathways. HIF-regulated genes involve in many pathological processes such as metabolic switch, drug efflux, angiogenesis, cell proliferation, and anti-apoptosis, which ultimately leads to increased tumor growth and drug resistance. Due to the common failure of classic chemotherapeutic agents in treating hypoxic cancers, novel strategies have been developed to target tumors under hypoxic conditions including inhibition of HIF activity and administration of bioreductive drugs. These new strategies may provide more effective and specific methods in targeting hypoxic tumors.

Routine defunctioning stoma after chemoradiation and total mesorectal excision: a single-surgeon experience.

AIM To investigate the 10-year results of treating low rectal cancer by a single surgeon in one institution. METHODS From Oct 1998 to Feb 2009, we prospectively followed a total of 62 patients with cT2-4 low rectal cancer with lower tumor margins measuring at 3 to 6 cm above the anal verge. All patients received neoadjuvant chemoradiation (CRT) for 6 wk. Among them, 85% of the patients received 225 mg/m(2)/d 5-fluorouracil using a portable infusion pump. The whole pelvis received a total dose of 45 Gy of irradiation in 25 fractions over 5 wk. The interval from CRT completion to surgical intervention was planned to be approximately 6-8 wk. Total mesorectal excision (TME) and routine defunctioning stoma construction were performed by one surgeon. The distal resection margin, circumferential resection margin, tumor regression grade (TRG) and other parameters were recorded. We used TRG to evaluate the tumor response after neoadjuvant CRT. We evaluated anal function outcomes using the Memorial Sloan-Kettering Cancer Center anal function scores after closure of the defunctioning stoma. RESULTS The median distance from the lower margin of rectal cancer to the anal verge was 5 cm: 6 cm in 9 patients, 5 cm in 32 patients, 4 cm in 10 patients, and 3 cm in 11 patients. Before receiving neoadjuvant CRT, 45 patients (72.6%) had a cT3-4 tumor, and 21 (33.9%) patients had a cN1-2 lymph node status. After CRT, 30 patients (48.4%) had a greater than 50% clinical reduction in tumor size. The final pathology reports revealed that 33 patients (53.2%) had a ypT3-4 tumor and 12 (19.4%) patients had ypN1-2 lymph node involvement. All patients completed the entire course of neoadjuvant CRT. Most patients developed only Grade 1-2 toxicities during CRT. Thirteen patients (21%) achieved a pathologic complete response. Few post-operative complications occurred. Nearly 90% of the defunctioning stomas were closed within 6 mo. The local recurrence rate was 3.2%. Pathologic lymph node involvement was the only prognostic factor predicting disease recurrence (36.5% vs 76.5%, P = 0.006). Nearly 90% of patients recovered sphincter function within 2 year after closure of the defunctioning stoma. CONCLUSION Neoadjuvant CRT followed by TME, combined with routine defunctioning stoma construction and high-volume surgeon experience, can provide excellent surgical quality and good local disease control.

Dynamic change of tetraspanin CD151 membrane protein expression in colorectal cancer patients.

Purpose: To measure the CD151 expression in colorectal cancer (CRC). Methods: CD151 expression was assessed in 179 CRC patients and 39 patients with hepatic liver metastasis. Results: High CD151 expression was observed in 48% of patients with early-stage CRC versus only 33% of patients with metastatic colon cancer. A higher level of tumor invasion status correlated with a decrease in CD151 expression. Metastatic stage and advanced tumor stage correlated with a decreased CD151 expression. Twenty-seven out of the 39-paired samples had high CD151 expression in liver metastasis sites. Conclusions: CD151 expression is decreased in patients with metastatic CRC.

Serrated adenocarcinoma morphology in colorectal mucinous adenocarcinoma is associated with improved patient survival

Colorectal mucinous adenocarcinoma (MAC) and serrated adenocarcinoma (SAC) share many characteristics, including right-side colon location, frequent mucin production, and various molecular features. This study examined the frequency of SAC morphology in MACs. We assessed the correlation of SAC morphology with clinicopathological parameters, molecular characteristics, and patient prognosis. Eighty-eight colorectal MACs were collected and reviewed for SAC morphology according to Makinens criteria. We sequenced KRAS and BRAF, assessed CpG island methylator phenotype (CIMP) frequency, and analyzed DNA mismatch repair enzyme levels using immunohistochemistry in tumor samples. SAC morphology was observed in 38% of MACs, and was associated with proximal location (P=0.001), BRAF mutation (P=0.042), CIMP-positive status (P=0.023), and contiguous traditional serrated adenoma (P=0.019). Multivariate analysis revealed that MACs without both SAC morphology and CIMP-positive status exhibited 3.955 times greater risk of cancer relapse than MACs having both characteristics or either one (P=0.035). Our results show that two MAC groups with distinct features can be identified using Makinens criteria, and suggest a favorable prognostic role for the serrated neoplastic pathway in colorectal MAC.

Numerous peritoneal loose bodies with ileus

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Six primary cancers in one lynch syndrome patient with chronic arsenic exposure

PO-CHUAN CHEN, MD, WEN-CHAU CHEN, MD, SHEAU-CHIOU CHAO, MD, BO-WEN LIN, MD, SHAO-CHIEH LIN, MD, CHIA-JUNG CHEN, RN, JENQ-CHANG LEE, MD* Division of Colorectal Surgery, Department of Surgery, National Cheng Kung University Hospital and College of Medicine, Tainan City, R.O.C., Taiwan Department of Emergency Medicine, National Cheng Kung University Hospital and College of Medicine, Tainan City, R.O.C., Taiwan Department of Dermatology, National Cheng Kung University Hospital and College of Medicine, Tainan City, R.O.C., Taiwan