Sox9 has gained increasing importance both functionally and as a prognostic factor in cancer. We demonstrate a functional role for Sox9 in inducing a mesenchymal phenotype in lung ADC. We show that Sox9 mRNA and protein are overexpressed in lung ADC, particularly those with KRAS mutations. Sox9 expression correlated with the Notch target gene Hes1, and numerous other Notch pathway components. We observed that Sox9 is a potent inducer of lung cancer cell motility and invasion, and a negative regulator of E-cadherin, a key protein that is lost during epithelial-mesenchymal transition (EMT). Moreover, we show that Notch1 signaling directly regulates Sox9 expression through a SOX9 promoter binding site, independently of the TGF-β pathway, and that Sox9 participates in Notch-1 induced cell motility, cell invasion, and loss of E-cadherin expression. Together, the results identify a new functional role for a Notch1-Sox9 signaling axis in lung ADC that may explain the correlation of Sox9 with tumor progression, higher tumor grade, and poor lung cancer survival. In addition to Notch and TGF-β, Sox9 also acts downstream of NF-κB and Wnt/β-catenin signaling. Thus, Sox9 could potentially act as a hub to mediate cross-talk among key oncogenic pathways in lung ADC. Targeting Sox9 expression or transcriptional activity could potentially reduce resistance to targeted therapy for lung ADC caused by pathway redundancy.
BackgroundBone morphogenetic proteins (BMP) are embryonic morphogens that are aberrantly expressed in lung cancer. BMPs mediate cell fate decisions and self-renewal of stem cells, through transcription regulation of inhibitor of differentiation protein/DNA binding proteins (Id1-3). Inhibition of BMP signaling decreases growth and induces cell death of lung cancer cells lines by downregulating the expression of Id proteins. It is not known whether the BMP signaling cascade regulates growth and the expression of Id proteins of lung cancer cells expressing the stem cell markers Oct4 and/or nestin.MethodsLung cancer cells expressing Oct4 or nestin were isolated from lung cancer cell lines by stably transfecting the Oct4 promoter or nestin promoter expression vectors that induce expression of the green fluorescent protein reporter.ResultsOur studies suggest that lung cancer cells expressing Oct4 or nestin are different cell populations. Microarray and quantitative RT-PCR demonstrated that the expression of specific stem cell markers were different between isolated Oct4 and nestin cells. Both the Oct4 and nestin populations were more tumorigenic than controls but histologically they were quite different. The isolated Oct4 and nestin cells also responded differently to inhibition of BMP signaling. Blockade of BMP signaling with the BMP receptor antagonist DMH2 caused significant growth inhibition of both the Oct4 and nestin cell populations but only increased cell death in the nestin population. DMH2 also induced the expression of nestin in the Oct4 population but not in the nestin cells. We also show that BMP signaling is an important regulator of Id1 and Id3 in both the Oct4 and nestin cell populations. Furthermore, we show that NeuN is frequently expressed in NSCLC and provide evidence suggesting that Oct4 cells give rise to cancer cells expressing nestin and/or NeuN.ConclusionThese studies show that although biologically different, BMP signaling is growth promoting in cancer cells expressing Oct4 or nestin. Inhibition of BMP signaling decreases expression of Id proteins and suppresses growth of cancer cells expressing Oct4 or Nestin. Small molecule antagonists of the BMP type I receptors represent potential novel drugs to target the population of cancer cells expressing stem cell markers.
Sarcoid-like granulomatous diseases (SGD) have been previously identified in cohorts of World Trade Center (WTC) dust-exposed individuals. In the present studies, we analyzed lung and/or lymph node biopsies from patients referred to our clinic with suspected WTC dust-induced lung disease to evaluate potential pathophysiologic mechanisms. Histologic sections of lung and/or lymph node samples were analyzed for markers of injury, oxidative stress, inflammation, fibrosis, and epigenetic modifications. Out of seven patients examined, we diagnosed four with SGD and two with pulmonary fibrosis; one was diagnosed later with SGD at another medical facility. Patients with SGD were predominantly white, obese men, who were less than 50 years old and never smoked. Cytochrome b5, cytokeratin 17, heme oxygenase-1, lipocalin-2, inducible nitric oxide synthase, cyclooxygenase 2, tumor necrosis factor α, ADP-ribosylation factor-like GTPase 11, mannose receptor-1, galectin-3, transforming growth factor β, histone-3 and methylated histone-3 were identified in lung and lymph nodes at varying levels in all samples examined. Three of the biopsy samples with granulomas displayed peri-granulomatous fibrosis. These findings are important and suggest the potential of WTC dust-induced fibrotic sarcoid. It is likely that patient demographics and/or genetic factors influence the response to WTC dust injury and that these contribute to different pathological outcomes.
Background: Churg-Strauss is a rare form of vasculitis characterized by pulmonary and small-vessel necrotizing vasculitis, vascular and/or extravascular granulomas, eosinophilia and tissue infiltration by eosinophils. Investigations: We Report a case of a patient with known history of this type of vasculitis who presented with severe right testicular pain. Scrotal sonogram evaluation revealed an associated hypoechoic lesion on his right testicle. Tumor markers (alpha-fetoprotein and β human chorionic gonadotropin) were within normal limits. Diagnosis: Differential diagnosis considered were tumor, hematoma and possible vasculitis involvement of the testis. Management: Secondary to persistent pain the patient elected to have surgery. Right orchiectomy was performed and final pathological evaluation of the lesion was consistent with infarct secondary to patient known vasculitis. Patient did well after surgery and is currently on steroid therapy for his underlying condition. Vasculitis involvement of the testis is rare and sonogram imaging does not differentiate well between a tumor and an infarct secondary to the vasculitis. In patient with negative tumor markers unless symptoms dictate otherwise a conservative approach can be taken and surgery avoid. This is the first case ever reported of Churg-Strauss syndrome involving the testicle.
Background: Follicular neoplasm (Bethesda IV cytology) requires thyroid lobectomy for diagnosis. Approximately 15-30% of cases are ultimately malignant, requiring reoperative completion thyroidectomy. We sought to reassess whether intraoperative frozen section (FS) reduces the need for reoperative thyroidectomy in these cases. Methods:A retrospective chart review of fine needle aspiration (FNA) results showing follicular neoplasm from 2003 to 2012 was performed. Our practice is to offer thyroid lobectomy with FS for these patients; with suspicious FS, surgery proceeded to total thyroidectomy. FS suspicious for papillary thyroid carcinoma (PTC) was based on nuclear features (nuclear grooves/atypia, pseudo-nuclear inclusions) and for follicular thyroid carcinoma (FTC) was based on capsular/vascular invasion. Results:A total of 148 patients with follicular neoplasm on FNA were identified, of which 79 underwent FS. Fifteen had suspicious FS with 12 having malignancy on final pathology, for a positive predictive value of 80%. Nine showed features suspicious for PTC, of which eight had PTC. Six showed features suspicious for FTC, of which four had malignancy on final pathology. Of the 64 patients with unremarkable FS, 49 had benign final pathology, for a negative predictive value of 77%. Twelve (19%) patients required reoperation. Seven of 19 patients (37%) with malignancy avoided reoperation due to FS. Risk of malignancy with follicular neoplasm diagnosis was 34% (51/148), while risk of malignancy with follicular neoplasm and suspicious FS was 80%. Conclusions:Risk of malignancy with follicular neoplasm and suspicious FS is 80%. FS may avoid reoperative completion thyroidectomy in up to a third of patients.
This paper analyses the clinical features of 8 patients with post-thrombotic obstruction of the subclavian and axillary veins demonstrated by phlebography. The classic physical signs of swelling of the arm with dilated superficial collateral veins were seen. The causes of thrombotic obstruction are discussed and the precipitating cause in this study was possibly filariasis.
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