MK615 Suppresses Hypoxia Tolerance by Up-regulation of E-cadherin in Colorectal Cancer Cells With Mutant KRAS.

BACKGROUND/AIM: The Japanese apricot "Prunus mume" is a traditional Japanese medicine. MK615, a compound extract from Prunus mume has been reported to have anti-tumor effects. Herein, we used 3D floating (3DF) culture to evaluate the anticancer effects of MK615 against human colorectal cancer (CRC) cells that contain mutant (mt) KRAS. MATERIALS AND METHODS: HKe3 cells exogenously expressing mtKRAS (HKe3-mtKRAS) were treated with MK615 in 3DF cultures. The protein levels of hypoxia-inducible factor 1 (HIF-1) and E-cadherin were quantified by western blotting. RESULTS: MtKRAS enhanced hypoxia tolerance via up-regulation of HIF-1. The expression of HIF-1 protein was suppressed by constitutive overexpression of E-cadherin in CRC HCT116 spheroids. MK615 increased the expression of E-cadherin and decreased the expression of HIF-1 in HKe3-mtKRAS. These results suggest that MK615 suppresses hypoxia tolerance by up-regulation of E-cadherin in CRC cells with mtKRAS. CONCLUSION: MK615 exhibits properties useful for the potential treatment of CRC patients with mtKRAS.

Gastric metastasis from salivary duct carcinoma mimicking primary gastric cancer.

INTRODUCTION: We present a very rare case of gastric metastasis mimicking primary gastric cancer in a patient who had undergone surgery for salivary duct carcinoma. PRESENTATION OF CASE: A 67-year-old man had been diagnosed as having right parotid cancer and had undergone a right parotidectomy and lymph node dissection. The histological diagnosis was salivary duct carcinoma. One year after the surgery, a positron emission tomography-computed tomography scan using fluorodeoxyglucose (FDG) revealed an abnormal uptake of FDG in the left cervical, mediastinal, paraaortic, and cardiac lymph nodes; stomach; and pancreas. On gastroduodenoscopy, there was a huge, easily bleeding ulcer mimicking primary gastric cancer at the upper body of the stomach. Biopsy revealed poorly differentiated adenocarcinoma. Therefore, we were unable to differentiate between the primary gastric cancer and the metastatic tumor using gastroduodenoscopy and biopsy. Because of the uncontrollable bleeding from the gastric cancer, we performed an emergency palliative total gastrectomy. On histological examination, the gastric lesion was found to be metastatic carcinoma originating from the salivary duct carcinoma. DISCUSSION: In the presented case, we could not diagnose the gastric metastasis originating from the salivary duct carcinoma even by endoscopic biopsy. This is because the histological appearance of salivary duct carcinoma is similar to that of high-grade adenocarcinoma, thus, resembling primary gastric cancer. CONCLUSION: When we perform endoscopic examination of patients with malignant neoplasias, a possibility of metastatic gastric cancer should be taken into consideration.

Proteolysis of EphA2 Converts It from a Tumor Suppressor to an Oncoprotein.

Eph receptor tyrosine kinases are considered candidate therapeutic targets in cancer, but they can exert opposing effects on cell growth. In the presence of its ligands, Eph receptor EphA2 suppresses signaling by other growth factor receptors, including ErbB, whereas ligand-independent activation of EphA2 augments ErbB signaling. To deploy EphA2-targeting drugs effectively in tumors, the anti-oncogenic ligand-dependent activation state of EphA2 must be discriminated from its oncogenic ligand-independent state. Because the molecular basis for the latter is little understood, we investigated how the activation state of EphA2 can be switched in tumor tissue. We found that ligand-binding domain of EphA2 is cleaved frequently by the membrane metalloproteinase MT1-MMP, a powerful modulator of the pericellular environment in tumor cells. EphA2 immunostaining revealed a significant loss of the N-terminal portion of EphA2 in areas of tumor tissue that expressed MT1-MMP. Moreover, EphA2 phosphorylation patterns that signify ligand-independent activation were observed specifically in these areas of tumor tissue. Mechanistic experiments revealed that processing of EphA2 by MT1-MMP promoted ErbB signaling, anchorage-independent growth, and cell migration. Conversely, expression of a proteolysis-resistant mutant of EphA2 prevented tumorigenesis and metastasis of human tumor xenografts in mice. Overall, our results showed how the proteolytic state of EphA2 in tumors determines its effector function and influences its status as a candidate biomarker for targeted therapy.

Tumor budding and laminin5-γ2 in squamous cell carcinoma of the external auditory canal are associated with shorter survival.

Squamous cell carcinoma (SCC) of the external auditory canal (EAC) is rare, usually presents at an advanced stage, and is a more aggressive tumor with poor prognosis. The University of Pittsburgh TNM staging system commonly used in prognostication is not perfect, and more accurate biomarkers predicting prognosis are needed. Tumor budding is an established negative prognostic factor at the invasive front in colorectal cancer. Moreover, immunohistochemical studies showed that laminin 5-γ2 (Ln5-γ2) is expressed at the invasive front in tumor or tumor budding cells. We assessed the prognostic significance of tumor budding and Ln5-γ2 expression by performing Ln5-γ2 immunohistochemistry and evaluated the degree of tumor budding in pre-treatment biopsy specimens, and investigated their correlations to clinicopathological parameters in patients with SCC of the EAC. Patients whose tumors had high budding grade and Ln5-γ2 expression had significantly shorter survival times. Budding grade was significantly correlated with Ln5-γ2 expression. Multivariate analysis revealed that high budding grade predicted poorer prognosis regardless of disease stage. Our results suggested that budding grade and Ln5-γ2 expression can be used as indicators of poor prognosis in patients with SCC of the EAC.

Free jejunal graft repair after pharyngolaryngo-esophagectomy-risk factor analysis for postoperative dysphagia.

PURPOSE: Reconstruction with free jejunal graft (FJG) has been widely accepted for patients undergone pharyngo-cervical esophageal resection. Those patients often suffer variety of complications regarding postoperative peros function. We investigated risk factors especially focused on the development of dysphagia after FJG reconstruction. METHODS: A retrospective analysis was conducted using clinical chart review of 30 consecutive patients who underwent reconstruction with a FJG after pharyngo-laryngoesophagectomy from 1995 to 2010. Mortality, morbidity, and postoperative dysphagia were investigated. Dysphagia was defined when the patients required enteral nutrition until later than 1 month postoperatively without any other complications, including anastomotic leakage, anastomotic stricture, FJG ischemic necrosis, and hospital death. Data on potential clinical factors were extracted and the relation of these variables to postoperative dysphagia was examined by univariate and multivariate analysis. RESULTS: There was one patient with hospital death over total 30 patients who deceased due to fatal postoperative bleeding from arterial anastomosis of FJG. Postoperative complications occurred in 14 patients (46.7%) those included respiratory complication in 5, anastomotic leakage 3, FJG ischemic necrosis 2, paralytic ileus 2, ischemic change of tracheostomy 2, anastomotic stricture 1 and dysphagia 9. Dysphagia was the most frequent in this series. Multivariate analysis demonstrated induction radiation (≥60 Gy) was independently significant factors for postoperative dysphagia. CONCLUSION: FJG reconstruction may be safe and functionally satisfactory surgical option after pharyngo-laryngo-esophagectomy. Postoperative dysphagia may be induced prior radiation therapy.

Advantage of early induction of opioid to control pain induced by irradiation in head and neck cancer patients.

OBJECTIVE: Although radiotherapy is effective for head and neck cancer patients, the local pain evoked by the irradiation itself reduces food intake and frequently halts the treatment. Thus, pain control is an important problem in radiotherapy for head and neck cancer. We performed to examine whether early induction of low-dose, opioid from mild pain improves dietary and caloric intake, while reducing weight loss. METHODS: The subjects were 43 patients who were hospitalized for head and neck cancer from 2004 to 2008. They were patients who underwent radiation treatment but those who did not undergo preoperative treatment. They were divided into two groups, depending on whether the pain was mild or moderate when an opioid was introduced (MILD and MODERATE, N=23 and 20, respectively). RESULTS: The visual analog scale scores for pain were significantly lower in the MILD than in the MODERATE group at between 25 and 50 Gy. The amount of oxycodone used for pain was significantly lower in the MILD than the MODERATE group. A regular diet was maintained for significantly longer in the MILD group. Caloric intake was significantly higher in the MILD group at over 20 Gy. Weight loss was significantly lower in the MILD group at over 20 Gy. The incidence of side effects was equal in both groups. CONCLUSION: Our results indicated that the introduction of opioids for mild pain during radiotherapy controls the level of pain, improving food intake in head and neck cancer patients.