MicroRNA-381 Represses ID1 and is Deregulated in Lung Adenocarcinoma

MicroRNAs are small, noncoding RNAs that suppress gene expression by binding to the 3' untranslated region (UTR) and thereby repress translation or decrease messenger RNA stability. Inhibitor of differentiation 1 (ID1) is a putative stem-cell gene involved in invasion and angiogenesis. We previously showed that ID1 is regulated by Src kinases, overexpressed in human lung adenocarcinoma, and targeted by Src-dependent microRNAs. The current study focused on the association between miR-381 and ID1 in lung adenocarcinoma.

High expression of octamer-binding transcription factor 4A, prominin-1 and aldehyde dehydrogenase strongly indicates involvement in the initiation of lung adenocarcinoma resulting in shorter disease-free intervals

The increasing relevance of the cancer stem cell (CSC) hypothesis and the impact of CSC-associated markers in the carcinogenesis of solid tumours may provide potential prognostic implications in lung cancer. We propose that a collective genetic analysis of established CSC-related markers will generate data to better define the role of putative CSCs in lung adenocarcinoma (LAC).

HMGA1 and HMGA2 protein expression correlates with advanced tumour grade and lymph node metastasis in pancreatic adenocarcinoma

Pancreatic ductal adenocarcinoma follows a multistep model of progression through precursor lesions called pancreatic intraepithelial neoplasia (PanIN). The high mobility group A1 (HMGA1) and high mobility group A2 (HMGA2) proteins are architectural transcription factors that have been implicated in the pathogenesis and progression of malignant tumours, including pancreatic cancer. The aim of this study was to explore the role of HMGA1 and HMGA2 in pancreatic carcinogenesis.

Factors predicting prognosis and recurrence in patients with esophago-gastric adenocarcinoma and histopathological response with less than 10 % residual tumor

PURPOSE: Neoadjuvant treatment is an accepted standard approach for treating locally advanced esophago-gastric adenocarcinomas. Despite a response of the primary tumor, a significant percentage dies from tumor recurrence. The aim of this retrospective exploratory study from two academic centers was to identify predictors of survival and recurrence in histopathologically responding patients. METHODS: Two hundred thirty one patients with adenocarcinomas (esophagus: n = 185, stomach: n = 46, cT3/4, cN0/+, cM0) treated with preoperative chemotherapy (n = 212) or chemoradiotherapy (n = 19) followed by resection achieved a histopathological response (regression 1a: no residual tumor (n = 58), and regression 1b < 10 % residual tumor (n = 173)). RESULTS: The estimated median overall survival was 92.4 months (5-year survival, 56.6 %) for all patients. For patients with regression 1a, median survival is not reached (5-year survival, 71.6 %) compared to patients with regression 1b with 75.3 months median (5-year survival, 52.2 %) (p = 0.031). Patients with a regression 1a had lymph node metastases in 19.0 versus 33.7 % in regression 1b. The ypT-category (p < 0.001), the M-category (p = 0.005), and the type of treatment (p = 0.04) were found to be independent prognostic factors in R0-resected patients. The recurrence rate was 31.7 % (n = 66) (local, 39.4 %; peritoneal carcinomatosis, 25.7 %; distant metastases, 50 %). Recurrence was predicted by female gender (p = 0.013), ypT-category (p = 0.007), and M-category (p = 0.003) in multivariate analysis. CONCLUSION: Response of the primary tumor does not guarantee recurrence-free long-term survival, but histopathological complete responders have better prognosis compared to partial responders. Established prognostic factors strongly influence the outcome, which could, in the future, be used for stratification of adjuvant treatment approaches. Increasing the rate of histopathological complete responders is a valid endpoint for future clinical trials investigating new drugs.

MALDI imaging mass spectrometry reveals COX7A2, TAGLN2 and S100-A10 as novel prognostic markers in Barrett's adenocarcinoma

To characterize proteomic changes found in Barrett's adenocarcinoma and its premalignant stages, the proteomic profiles of histologically defined precursor and invasive carcinoma lesions were analyzed by MALDI imaging MS. For a primary proteomic screening, a discovery cohort of 38 fresh frozen Barrett's adenocarcinoma patient tissue samples was used. The goal was to find proteins that might be used as markers for monitoring cancer development as well as for predicting regional lymph node metastasis and disease outcome. Using mass spectrometry for protein identification and validating the results by immunohistochemistry on an independent validation set, we could identify two of 60 differentially expressed m/z species between Barrett's adenocarcinoma and the precursor lesion: COX7A2 and S100-A10. Furthermore, among 22 m/z species that are differentially expressed in Barrett's adenocarcinoma cases with and without regional lymph node metastasis, one was identified as TAGLN2. In the validation set, we found a correlation of the expression levels of COX7A2 and TAGLN2 with a poor prognosis while S100-A10 was confirmed by multivariate analysis as a novel independent prognostic factor in Barrett's adenocarcinoma. Our results underscore the high potential of MALDI imaging for revealing new biologically significant molecular details from cancer tissues which might have potential for clinical application. This article is part of a Special Issue entitled: Translational Proteomics.

Junctional adhesion molecule (JAM)-C deficient C57BL/6 mice develop a severe hydrocephalus

The junctional adhesion molecule (JAM)-C is a widely expressed adhesion molecule regulating cell adhesion, cell polarity and inflammation. JAM-C expression and function in the central nervous system (CNS) has been poorly characterized to date. Here we show that JAM-C(-/-) mice backcrossed onto the C57BL/6 genetic background developed a severe hydrocephalus. An in depth immunohistochemical study revealed specific immunostaining for JAM-C in vascular endothelial cells in the CNS parenchyma, the meninges and in the choroid plexus of healthy C57BL/6 mice. Additional JAM-C immunostaining was detected on ependymal cells lining the ventricles and on choroid plexus epithelial cells. Despite the presence of hemorrhages in the brains of JAM-C(-/-) mice, our study demonstrates that development of the hydrocephalus was not due to a vascular function of JAM-C as endothelial re-expression of JAM-C failed to rescue the hydrocephalus phenotype of JAM-C(-/-) C57BL/6 mice. Evaluation of cerebrospinal fluid (CSF) circulation within the ventricular system of JAM-C(-/-) mice excluded occlusion of the cerebral aqueduct as the cause of hydrocephalus development but showed the acquisition of a block or reduction of CSF drainage from the lateral to the 3(rd) ventricle in JAM-C(-/-) C57BL/6 mice. Taken together, our study suggests that JAM-C(-/-) C57BL/6 mice model the important role for JAM-C in brain development and CSF homeostasis as recently observed in humans with a loss-of-function mutation in JAM-C.

Factors influencing outcome in patients undergoing portal vein resection for adenocarcinoma of the pancreas

Survival rates after surgery and adjuvant chemotherapy for pancreatic ductal adenocarcinoma (PDA) remain low. Selected patients with portal/superior mesenteric vein (PV) involvement undergo PV resection at pancreaticoduodenectomy (PD). This study analyses outcomes for PD with/without PV resection in patients with PDA.

Higher frequency of chromosomal aberrations in ovarian endometriosis compared to extragonadal endometriosis: A possible link to endometrioid adenocarcinoma

Endometriosis may progress to invasive endometrioid adenocarcinoma, particularly in the ovary. Up to now, little is known of the molecular mechanisms possibly involved in the malignant transformation of endometriosis. Therefore, in this study, extragonadal endometriosis (n = 10), ovarian endometriosis without malignancy (n = 10), ovarian endometriosis with direct transition into endometrioid adenocarcinoma (n = 8), and normal endometrium (n = 12) were investigated for numerical chromosomal aberrations by fluorescence in situ hybridization using centromere enumeration probes. The proportions of cells with aneusomies were semiquantitatively assessed. Trisomies 1 and 7, and monosomies 9 and 17 were found in endometriosis, ovarian endometrioid adenocarcinoma, and normal endometrium. The proportions of aneusomic cells were significantly higher in ovarian endometrioid carcinoma compared with ovarian endometriosis (P < 0.001), and in ovarian endometriosis compared with extragonadal endometriosis and normal endometrium (P < 0.001). The data provide new evidence of a common lineage of endometriosis and ovarian endometrioid carcinoma. The higher frequency of chromosomal aberrations in endometrioid carcinoma than in endometriosis may reflect an expansion of aberrant cell clones already present in endometriosis during the progression to cancer. The higher frequency of chromosomal aberrations in ovarian endometriosis than in extragonadal endometriosis suggests a role of the ovarian stromal milieu in the induction of genetic changes, which may eventually lead to invasive cancer.

Adenocarcinoma metastasis of the intertransversarius cervicis muscle eliciting a right forelimb lameness in a dog

This article describes identification of a metastatic adenocarcinoma to the intertransversarius cervicis muscle using magnetic resonance imaging (MRI) in a dog that presented with chronic lameness of the right forelimb. Magnetic resonance imaging revealed a right sided, ovoid signal abnormality within the intertransversarius cervicis muscle lateral to the sixth cervical (C6) vertebra. The lesion was uniform, hyperintense on T2- and isointense on T1-weighted images to muscle and exhibited uniform contrast enhancement on T1-weighted images. The MRI findings were consistent with a neoplasia. Surgical excision was performed. Histopathological diagnosis was metastatic fibrous adenocarcinoma. The dog recovered rapidly but 6 months post-operatively he was killed because of lung metastases. Necropsy was declined and the primary tumour could not be identified.

Exophytic mass of the gingiva as the first manifestation of metastatic pulmonary adenocarcinoma

BACKGROUND: Metastasis of a malignant tumor to the oral cavity is rare, but it can be the first manifestation of a primary tumor. METHODS: The clinicopathologic features of a gingival metastasis originating from lung adenocarcinoma in a female patient are described. A 57-year-old woman showed a rapidly growing, painless, exophytic mass in the left mandibular gingiva. The whole lesion was excised, and histologic and immunohistochemical analyses were performed. RESULTS: The histopathologic sections showed a proliferation of poorly differentiated spindle and pleomorphic cells. Because the differentiation between carcinoma and sarcoma of spindle cell tumors was difficult, additional immunohistochemical evaluation was performed. The intraoral healing after tumor removal was uneventful. The discrepancy between the histopathologic results and the clinical findings led to a thorough examination by the patient's physician. Finally, a biopsy of the lungs confirmed a poorly differentiated adenocarcinoma with multiple metastases, including the oral cavity. CONCLUSIONS: An exophytic lesion on the gingiva can be the first sign of metastatic adenocarcinoma to the oral mucosa. This case emphasizes that even apparently benign-looking gingival lesions in anamnestically healthy patients need to be examined histopathologically.

Imaging Diagnosis - Lack of Contrast Enhancement in Metastatic Cerebral Adenocarcinoma

A 7-year-old female spayed Scottish Terrier was presented with central nervous system symptoms suggestive of a lesion in the forebrain. Magnetic resonance (MR) imaging revealed multifocal disease in the forebrain. Because of complete lack of contrast enhancement, the changes were attributed to lesions of inflammatory origin.Histopathology of the brain revealed multiplemetastatic lesions of an adenocarcinoma. Brainmetastases in general show contrast enhancement. The reason for a complete absence of contrast enhancement is unknown. Previous administration of corticosteroids, increased diffusion time of contrast medium, increased intracranial pressure in combination with an intact blood–tumor barrier is discussed as possible reasons.

Protective autophagy is involved in resistance towards MET inhibitors in human gastric adenocarcinoma cells

MET, also known as hepatocyte growth factor receptor (HGFR), is a receptor tyrosine kinase with an important role, both in normal cellular function as well as in oncogenesis. In many cancer types, abnormal activation of MET is related to poor prognosis and various strategies to inhibit its function, including small molecule inhibitors, are currently in preclinical and clinical evaluation. Autophagy, a self-digesting recycling mechanism with cytoprotective functions, is induced by cellular stress. This process is also induced upon cytotoxic drug treatment of cancer cells and partially allows these cells to escape cell death. Thus, since autophagy protects different tumor cells from chemotherapy-induced cell death, current clinical trials aim at combining autophagy inhibitors with different cancer treatments. We found that in a gastric adenocarcinoma cell line GTL-16, where MET activity is deregulated due to receptor overexpression, two different MET inhibitors PHA665752 and EMD1214063 lead to cell death paralleled by the induction of autophagy. A combined treatment of MET inhibitors together with the autophagy inhibitor 3-MA or genetically impairing autophagy by knocking down the key autophagy gene ATG7 further decreased cell viability of gastric cancer cells. In general, we observed the induction of cytoprotective autophagy in MET expressing cells upon MET inhibition and a combination of MET and autophagy inhibition resulted in significantly decreased cell viability in gastric cancer cells.

Suppression of OCT4B enhances sensitivity of lung adenocarcinoma A549 cells to cisplatin via increased apoptosis

BACKGROUND Resistance to chemotherapy in lung adenocarcinoma remains a major obstacle. We examined the potential role of Octamer-binding transcription factor-4B (OCT4B) in enhancing sensitivity of lung adenocarcinoma cells to cisplatin. MATERIALS AND METHODS RNAi interference was used to examine the role of OCT4B in cisplatin-treated A549 cells. Cells were transfected with OCT4B siRNA prior to a 48-h cisplatin treatment. Propidium iodide (PI) and caspase-3 staining were used to determine cell viability and apoptosis. Cell-cycle analysis was performed to evaluate alterations in phase distribution. RESULTS OCT4B suppression in cells increased the number of non-viable, PI(+), and apoptotic, caspase-3(+) cells in the presence and absence of cisplatin treatment. Importantly, cisplatin treatment of OCT4B-suppressed cells resulted in a marked transition of cells from G0/G1 to G2/M phase. CONCLUSION Silencing of OCT4B confers sensitivity to cisplatin treatment in A549 cells via cell-cycle regulation, increased proliferation and enhancement of cisplatin-induced apoptosis. OCT4B clearly protects A549 cells from apoptosis.

Mucin-producing adenocarcinoma arising in an atrial myxoma

We describe the unique autopsy findings of a patient who died of a metastasizing giant right atrial adenocarcinoma containing few areas of typical myxoma. That no mucin-producing extracardiac tumor was detected pointed to the atrial adenocarcinoma as being the primary. We hypothesize that the adenocarcinoma may have developed from coexistent bland glandular structures within the myxoma.

Clinical response to chemotherapy in oesophageal adenocarcinoma patients is linked to defects in mitochondria

Chemotherapeutic drugs kill cancer cells, but it is unclear why this happens in responding patients but not in non-responders. Proteomic profiles of patients with oesophageal adenocarcinoma may be helpful in predicting response and selecting more effective treatment strategies. In this study, pretherapeutic oesophageal adenocarcinoma biopsies were analysed for proteomic changes associated with response to chemotherapy by MALDI imaging mass spectrometry. Resulting candidate proteins were identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and investigated for functional relevance in vitro. Clinical impact was validated in pretherapeutic biopsies from an independent patient cohort. Studies on the incidence of these defects in other solid tumours were included. We discovered that clinical response to cisplatin correlated with pre-existing defects in the mitochondrial respiratory chain complexes of cancer cells, caused by loss of specific cytochrome c oxidase (COX) subunits. Knockdown of a COX protein altered chemosensitivity in vitro, increasing the propensity of cancer cells to undergo cell death following cisplatin treatment. In an independent validation, patients with reduced COX protein expression prior to treatment exhibited favourable clinical outcomes to chemotherapy, whereas tumours with unchanged COX expression were chemoresistant. In conclusion, previously undiscovered pre-existing defects in mitochondrial respiratory complexes cause cancer cells to become chemosensitive: mitochondrial defects lower the cells' threshold for undergoing cell death in response to cisplatin. By contrast, cancer cells with intact mitochondrial respiratory complexes are chemoresistant and have a high threshold for cisplatin-induced cell death. This connection between mitochondrial respiration and chemosensitivity is relevant to anticancer therapeutics that target the mitochondrial electron transport chain.