ABCB1 inhibition provides a novel therapeutic target to block TWIST1-induced migration in medulloblastoma.

BACKGROUND: Therapeutic intervention in metastatic medulloblastoma is dependent on elucidating the underlying metastatic mechanism. We investigated whether an epithelial-mesenchymal transition (EMT)-like pathway could drive medulloblastoma metastasis. METHODS: A 3D Basement Membrane Extract (3D-BME) model was used to investigate medulloblastoma cell migration. Cell line growth was quantified with AlamarBlue metabolic assays and the morphology assessed by time-lapse imaging. Gene expression was analyzed by qRT-PCR and protein expression by immunohistochemistry of patient tissue microarrays and mouse orthotopic xenografts. Chromatin immunoprecipitation was used to determine whether the EMT transcription factor TWIST1 bound to the promoter of the multidrug pump ABCB1. TWIST1 was overexpressed in MED6 cells by lentiviral transduction (MED6-TWIST1). Inhibition of ABCB1 was mediated by vardenafil, and TWIST1 expression was reduced by either Harmine or shRNA. RESULTS: Metastatic cells migrated to form large metabolically active aggregates, whereas non-tumorigenic/non-metastatic cells formed small aggregates with decreasing metabolic activity. TWIST1 expression was upregulated in the 3D-BME model. TWIST1 and ABCB1 were significantly associated with metastasis in patients (P = .041 and P = .04, respectively). High nuclear TWIST1 expression was observed in the invasive edge of the MED1 orthotopic model, and TWIST1 knockdown in cell lines was associated with reduced cell migration (P < .05). TWIST1 bound to the ABCB1 promoter (P = .03) and induced cell aggregation in metastatic and TWIST1-overexpressing, non-metastatic (MED6-TWIST1) cells, which was significantly attenuated by vardenafil (P < .05). CONCLUSIONS: In this study, we identified a TWIST1-ABCB1 signaling axis during medulloblastoma migration, which can be therapeutically targeted with the clinically approved ABCB1 inhibitor, vardenafil.

Corrigendum to: ABCB1 inhibition provides a novel therapeutic target to block TWIST1-induced migration in medulloblastoma.

[This corrects the article DOI: 10.1093/noajnl/vdab030.].

Squamous cell carcinoma of the thyroid gland in an elderly female presenting as a rapidly enlarging thyroid mass.

BACKGROUND: Squamous cell carcinoma of the thyroid gland is an extremely rare tumor with a very aggressive clinical behavior and poor prognosis. The tumor may arise as a primary tumor within the thyroid gland or as a component of anaplastic or undifferentiated thyroid tumors. CASE PRESENTATION: A 70-year-old lady with history of long standing multinodular goiter presented with progressive enlargement of a midline nodule for 3 months which was associated with dyspnea and dry cough. The mass was hard and fixed. The voice was normal, other parts of the general examination were unremarkable. Fine needle aspiration was done for the mass which revealed malignant cells mixed with inflammatory cells. During surgery there was a hard and fixed mass arising from the isthmus of the thyroid gland that was locally invading, complete excision was not possible, debulking was done. Histopathology showed moderately differentiated squamous cell carcinoma of the thyroid gland. The tumor underwent local progression 6 months later and the patient was sent for radiotherapy. CONCLUSION: When thyroid tumor is advanced at time of diagnosis, radiotherapy is the main form of treatment which may induce reduction in the size of the tumor and decrease pain, radiotherapy may also be given on neoadjuvant bases which may render resection possible in some patients. The tumor is usually not responsive to chemotherapy. The overall survival is uniformly poor regardless of the primary form of treatment, the median survival of the patients from the time of diagnosis is few months in most cases.

Overcoming multiple drug resistance mechanisms in medulloblastoma.

INTRODUCTION: Medulloblastoma (MB) is the most common malignant paediatric brain tumour. Recurrence and progression of disease occurs in 15-20% of standard risk and 30-40% of high risk patients. We analysed whether circumvention of chemoresistance pathways (drug export, DNA repair and apoptotic inhibition) can restore chemotherapeutic efficacy in a panel of MB cell lines. RESULTS: We demonstrate, by immunohistochemistry in patient tissue microarrays, that ABCB1 is expressed in 43% of tumours and is significantly associated with high-risk. We show that ABCB1, O6-methylguanine-DNA-methyltransferase (MGMT) and BCL2 family members are differentially expressed (by quantitative reverse transcription polymerase chain reaction, Western blotting and flow cytometry) in MB cell lines. Based on these findings, each pathway was then inhibited or circumvented and cell survival assessed using clonogenic assays. Inhibition of ABCB1 using vardenafil or verapamil resulted in a significant increase in sensitivity to etoposide in ABCB1-expressing MB cell lines. Sensitivity to temozolomide (TMZ) was MGMT-dependent, but two novel imidazotetrazine derivatives (N-3 sulfoxide and N-3 propargyl TMZ analogues) demonstrated ≥7 fold and ≥3 fold more potent cytotoxicity respectively compared to TMZ in MGMT-expressing MB cell lines. Activity of the BAD mimetic ABT-737 was BCL2A1 and ABCB1 dependent, whereas the pan-BCL2 inhibitor obatoclax was effective as a single cytotoxic agent irrespective of MCL1, BCL2, BCL2A1, or ABCB1 expression. CONCLUSIONS: ABCB1 is associated with high-risk MB; hence, inhibition of ABCB1 by vardenafil may represent a valid approach in these patients. Imidazotetrazine analogues of TMZ and the BH3 mimetic obatoclax are promising clinical candidates in drug resistant MB tumours expressing MGMT and BCL2 anti-apoptotic members respectively.

Cancer incidence rates in the Kurdistan region/Iraq from 2007-2009.

Cancer is a disease of gradual increase in incidence overall the world. Kurdistan Region in Iraq has been exposed to several carcinogenic hazards. There are few reports about the increased risk of cancer in different cities in Iraq. These reports did not cover Kurdistan region. The aim of this paper was to study cancer incidence and to identify possible risks of cancer in this region. Cancer registries from 9 hospitals in three cities of Kurdistan were used as a source of data. Information on these cases was subjected to careful verification regarding repetition, place of residence and other possible errors. Overall registered cases in 2007, 2008 and 2009 were 1444, 2081, 2356 respectively. 49% of registered cases were males and 51% were female. The Age Standardized Rate of cancer was 89.83/100 000 among male and 83.93/100 000 among female. The results showed major variation in incidence rates of different types of cancer in the three governorates of Kurdistan. Furthermore, there was evidence of increased risks of cancer in Kurdistan Region in Iraq. Hematological malignancies were the most common cancer among male (21.13% of all cancer in males) and second most common in female (18.8% of all cancer in female), only exceeded by breast cancer. To reach sound conclusions about extent and determinants of cancer in Kurdistan, enormous multi-spectrum efforts are now needed.