Stephan C. Schäfer

Reduced expression of Hugl-1, the human homologue of Drosophila tumour suppressor gene lgl, contributes to progression of colorectal cancer.

The human gene, human giant larvae (Hugl-1/Llg1/Lgl1) has significant homology to the Drosophila tumour suppressor gene lethal(2)giant larvae (lgl). The lgl gene codes for a cortical cytoskeleton protein, Lgl, that binds Myosin II and is involved in maintaining cell polarity and epithelial integrity. The human protein, Hugl-1 contains several conserved functional domains found in Lgl, suggesting that these proteins may have closely related functions. Whether loss of Hugl expression plays a role in human tumorigenesis has so far not been extensively investigated. Thus, we evaluated tumour tissues from 94 patients undergoing surgery for colorectal cancer (CRC) for loss of Hugl-1 transcription and compared our findings with the clinical data from each of these patients. We found that Hugl-1 was lost in 75% of tumour samples and these losses were associated with advanced stage and particularly with lymph node metastases. Reduced Hugl-1 expression during the adenoma-carcinoma sequence occurring as early as in colorectal adenomas was detected by both immunohistochemical and reverse transcription–polymerase chain reaction analysis. Functional assays with ecdysone-inducible cell lines revealed that Hugl-1 expression increased cell adhesion and decreased cell migration. Our studies thus indicate that downregulation of Hugl-1 contributes to CRC progression.

miR-29b Mediates NF-κB Signaling in KRAS-Induced Non–Small Cell Lung Cancers

A global understanding of miRNA function in EGFR signaling pathways may provide insights into improving the management of KRAS-mutant lung cancers, which remain relatively recalcitrant to treatment. To identify miRNAs implicated in EGFR signaling, we transduced bronchial epithelial BEAS-2B cells with retroviral vectors expressing KRAS(G12V) and monitored miRNA expression patterns by microarray analysis. Through this approach, we defined miR-29b as an important target for upregulation by mutant KRAS in non-small cell lung cancers. Cell biologic analyses showed that pharmacologic inhibition of EGFR or MEK was sufficient to reduce levels of miR-29b, while PI3K inhibition had no effect. In KRAS(G12V)-transduced BEAS-2B cells, introduction of anti-miR-29b constructs increased the sensitivity to apoptosis, arguing that miR-29b mediated apoptotic resistance conferred by mutant KRAS. Mechanistic investigations traced this effect to the ability of miR-29b to target TNFAIP3/A20, a negative regulator of NF-κB signaling. Accordingly, overexpression of an miR-29b-refractory isoform of TNFAIP3 restored NF-κB and extrinsic apoptosis, confirming that TNFAIP3 is a functionally relevant target of miR-29b. We also noted that miR-29b could confer sensitivity to intrinsic apoptosis triggered by exposure to cisplatin, a drug used widely in lung cancer treatment. Thus, miR-29b expression may tilt cells from extrinsic to intrinsic mechanisms of apoptosis. Overall, our results reveal a complexity in cancer for miR-29b, which can act as either an oncogene or tumor suppressor gene depending on signaling context. Cancer Res; 76(14); 4160-9. ©2016 AACR.

Impact of salt on cardiac differential gene expression and coronary lesion in normotensive mineralocorticoid-treated mice

We previously reported that excess of deoxycorticosterone-acetate (DOCA)/salt-induced cardiac hypertrophy in the absence of hypertension in one-renin gene mice. This model allows us to study molecular mechanisms of high-salt intake in the development of cardiovascular remodeling, independently of blood pressure in a high mineralocorticoid state. In this study, we compared the effect of 5-wk low- and high-salt intake on cardiovascular remodeling and cardiac differential gene expression in mice receiving the same amount of DOCA. Differential gene and protein expression was measured by high-density cDNA microarray assays, real-time PCR and Western blot analysis in DOCA-high salt (HS) vs. DOCA-low salt (LS) mice. DOCA-HS mice developed cardiac hypertrophy, coronary perivascular fibrosis, and left ventricular dysfunction. Differential gene and protein expression demonstrated that high-salt intake upregulated a subset of genes encoding for proteins involved in inflammation and extracellular matrix remodeling (e.g., Col3a1, Col1a2, Hmox1, and Lcn2). A major subset of downregulated genes encoded for transcription factors, including myeloid differentiation primary response (MyD) genes. Our data provide some evidence that vascular remodeling, fibrosis, and inflammation are important consequences of a high-salt intake in DOCA mice. Our study suggests that among the different pathogenic factors of cardiac and vascular remodeling, such as hypertension and mineralocorticoid excess and sodium intake, the latter is critical for the development of the profibrotic and proinflammatory phenotype observed in the heart of normotensive DOCA-treated mice.

Cytokeratin-positive epithelioid gastrointestinal stromal tumor of the stomach - a comment on "gastric undifferentiated carcinoma with diffuse c-kit overexpression and focal neuroendocrine differentiation".

We read with much interest the report by Mori and colleagues ntitled “Gastric undifferentiated carcinoma with diffuse c-kit verexpression and focal neuroendocrine differentiation” [2]. The uthors describe the case of a 76-year-old male patient undergoing esection of a gastric tumor described as an “exophytic noduar mass with central ulceration at the gastric prepylorus”. The hotographically documented gross findings may suggest the posibility of a gastrointestinal stromal tumor (GIST) to the reader. f note, none of 42 resected lymph nodes was involved, which – iven the size of the tumor – would be somewhat more consisent with the expected behavior of a GIST than that of a gastric arcinoma. Indeed, the differential diagnosis of a GIST was pertinently uled in by Mori et al. on account of their finding of widespread mmunoreactivity for c-kit in the tumor cells. The authors neverheless conclude that diffuse positivity for pan-cytokeratin marker E1/AE3 – as well as focal positivity for synaptophysin and chroogranin A – along with the absence of an identified mutation in he KIT gene (encoding c-kit) are more consistent with an undiferentiated carcinoma with aberrant c-kit immunoreactivity (and ocal neuroendocrine differentiation). We believe that on account of the findings summarized above n alternative conclusion is possible – and would like to illusrate our point with a recent case from our practice. A 78-year-old ale underwent gastroscopic biopsy of a mass described as suspicious for ulcerated gastric carcinoma” by the referring endocopist. Histologically, several tiny fragments of poorly cohesive edium-sized cells with scant cytoplasm were present. The iniial differential diagnosis included undifferentiated carcinoma and ymphoma. Tumor cells, however, failed to show immunoreactivity or lymphoid markers (CD3, CD20, CD45) while only a small perentage of tumor cells featured dot-like or globular positivity for

Myoepithelioma of the cerebellopontine angle: a previously not documented benign salivary gland-type neoplasm within the cranium.

Myoepithelioma is a dimorphic neoplasm with contractile-epithelial phenotype, originally interpreted as deriving from, but not actually restricted to the salivary glands. As a novel addition to the list of exquisitely rare intracranial salivary gland-type tumors and tumor-like lesions, we report on an example of myoepithelioma encountered in the left cerebellopontine angle of a 32-year-old male. Clinically presenting with ataxia and dizziness, this extraaxial mass of 4 × 3.5 × 3 cm was surgically resected, and the patient is alive 6 years postoperatively. Histologically, the tumor exhibited a continuum ranging from compact fascicles of spindle cells to epithelial nests and trabeculae partitioned by hyalinized septa, while lacking tubular differentiation. Regardless of architectural variations, there was robust immunoexpression of S100 protein, smooth muscle actin, GFAP, cytokeratin, and vimentin. Cytologic atypia tended to be modest throughout, and the MIB1 labeling index averaged less than 1%. Fluorescent in situ hybridization indicated no rearrangement of the EWSR1 locus. We interpret these results to suggest that myoepithelioma of the posterior fossa - along with related salivary epithelial tumors in this ostensibly incongruous locale - may possibly represent analogous neoplasms to their orthotopic counterparts, ones arising within aberrant salivary anlagen. The presence of the latter lends itself to being mechanistically accounted for by either postulating placodal remnants in the wake of branchial arch development, or linking them to exocrine glandular nests within endodermal cysts. Alternatively, myoepithelioma at this site could be regarded as a non tissue-specific lesion similar to its relatives ubiquitously occurring in the soft parts.

Krebsentstehung und Differenzierung

Die Konfrontation der Wissenschaftler in der Grundlagenforschung mit dem Krebsproblem hat in den letzten Jahren zu einer Fulle neuer Erkenntnisse und zu neuen Denk- und Forschungsansatzen gefuhrt. Wahrend die Auswahl der erfolgversprechenden Forschungsansatze fruher eher ungerichtet und zufallig erfolgte, das heist von einzelnen Beobachtungen von Unterschieden normaler und maligner Zellen ausging, konnen seit einigen Jahren die Krebserkrankungen nun auch gezielt nach bestimmten grundlegenden zell- und molekularbiologischen Prinzipien erforscht werden.