Houda Alatassi

Inhibition of AKT promotes FOXO3a-dependent apoptosis in prostate cancer

Growth factor-induced activation of protein kinase-B (PKB), also known as AKT, induces pro-survival signaling and inhibits activation of pro-apoptotic signaling molecules including the Forkhead box O-3a (FOXO3a) transcription factor and caspase in transformed prostate cells in vitro. Earlier we reported that Withaferin-A (WA), a small herbal molecule, induces pro-apoptotic response-4 (Par-4) mediated apoptosis in castration-resistant prostate cancer (CRPC) cells. In the present study, we demonstrate that inhibition of AKT facilitates nuclear shuttling of FOXO3a where it regulates Par-4 transcription in CRPC cells. FOXO3a is upstream of Par-4 signaling, which is required for induction of apoptosis in CRPC cells. Promoter bashing studies and Ch-IP analysis confirm a direct interaction of FOXO3a and Par-4; a sequential deletion of FOXO3a-binding sites in the Par-4 promoter fails to induce Par-4 activation. To confirm these observations, we either overexpressed AKT or silenced FOXO3a activation in CRPC cells. Both methods inhibit Par-4 function and apoptosis is significantly compromised. In xenograft tumors derived from AKT-overexpressed CRPC cells, FOXO3a and Par-4 expression is downregulated, leading to aggressive tumor growth. Oral administration of WA to mice with xenograft tumors restores FOXO3a-mediated Par-4 functions and results in inhibited tumor growth. Finally, an inverse correlation of nuclear localization of AKT expression corresponds to cytoplasmic Par-4 localization in human prostate tissue array. Our studies suggest that Par-4 is one of the key transcriptional targets of FOXO3a, and Par-4 activation is required for induction of apoptosis in CRPC cells. Activation of FOXO3a appears to be an attractive target for the treatment of CRPC and molecules such as WA can be explored further for the treatment of CRPC.

Rosai-Dorfman Disease of the Gastrointestinal Tract: Report of a Case and Review of the Literature

Rosai-Dorfman disease (RDD) is a rare, acquired disease of unknown etiology that affects primarily children and young adults. It is characterized by a proliferation of distinctive histiocytes in the lymph nodes and/or extranodal sites. Involvement of the gastrointestinal tract is rare. We report a case of RDD in a 60-year-old woman who presented with hematochezia and was found to have RDD of the rectum presenting as a rectal mass. This report highlights the current pathogenetic mechanisms, immunohistochemical markers, and the gastrointestinal manifestations of RDD.

Impact of immediate evaluation of touch imprint cytology from computed tomography guided core needle biopsies of mass lesions: Single institution experience

Background: Computed tomography (CT) guided core needle biopsy (CT-guided CNB) is a minimally invasive, safe and effective manner of tissue sampling in many organs. The aim of our study is to determine the impact of on-site evaluation of touch imprint cytology (TIC) to minimize the number of passes required to obtain adequate tissue for diagnosis. Design: A retrospective review of all CT-guided CNBs performed during 4 year period, where pathologists were present for on-site TIC evaluation. Each case was evaluated for the number of passes required before TIC was interpreted as adequate for diagnosis. Results: A total of 140 CT-guided CNBs were included in the study (liver, lung, kidney, sacral, paraspinal, omental, splenic and adrenal masses). Of the 140 cases, 109 were diagnosed as malignant, 28 as benign and three insufficient. In 106 cases (75.7%), the biopsies were determined adequate by TIC on the first pass, 19 cases (13%) on the second pass and 7 cases (5%) on the third pass. Only in 5 cases (3.6%), more than three passes were required before diagnostic material was obtained. Three cases (2.14%) were interpreted as inadequate both on TIC and on the final diagnosis. Of the biopsies deemed adequate on the first pass, 71% resulted in either termination of the procedure, or only one additional pass was obtained. In five cases, based on the TIC evaluation, a portion of the sample was sent for either flow cytometric analysis or cytogenetic studies. Conclusions: In the majority of cases, adequate material was obtained in the first pass of CT-guided CNB and once this was obtained, either no additional passes, or one additional pass was performed. This study demonstrates the utility of on-site evaluation in minimizing the number of passes required for obtaining adequate diagnostic material and for proper specimen triage for ancillary studies, which in turn decreases the risk to the patient and costs. However, tumor exhaustion in the tissue as a result of TIC is an important pitfall of the procedure, which occurred in 9 (8.2%) of our malignant cases.

Epithelioid angiomyolipoma of the liver with striking giant cell component: Fine‐needle aspiration biopsy findings of a rare neoplasm

Angiomyolipoma (AML) is a uncommon benign neoplasm of the liver with cyto‐ and histologic features similar to the more commonly encountered renal AML. Tumors composed predominantly of epithelioid cells have been referred to as epithelioid AML. Because most liver lesions are first evaluated by fine‐needle aspiration biopsy (FNAB), it is important to distinguish this variant of AML from more common hepatic neoplasms such as hepatocellular carcinoma (HCC) or metastatic tumors. Rare reports of epithelioid AML of the liver diagnosed by FNAB are in the literature. Here, we describe the cytologic findings of a unique case of epithelioid AML with numerous giant cells. Diagn. Cytopathol. 2009.

Oral administration of withaferin A inhibits carcinogenesis of prostate in TRAMP model

We previously reported that withaferin A (WA), a natural compound, deters prostate cancer by inhibiting AKT while inducing apoptosis. In the current study, we examined its chemopreventive efficacy against carcinogenesis in the prostate using the transgenic adenocarcinoma of mouse prostate (TRAMP) model. Two distinct sets of experiments were conducted. To determine whether WA delays tumor progression, it was given before cancer onset, at week 6, and until week 44. To determine its effect after the onset of prostate cancer, it was given from weeks 12 to 35. In both strategies, oral administration of WA effectively suppressed tumor burden when compared to vehicle-treated animals. No toxicity was seen in treated animals at gross pathological examination. Western blot analysis and immunohistochemistry of tumor sections revealed that in TRAMP controls, AKT and pAKT were highly expressed while nuclear FOXO3a and Par-4 were downregulated. On the contrary, treated mice showed inhibition of AKT signaling and activation of FOX03a-Par-4-induced cell death. They also displayed inhibition of mesenchymal markers such as β-catenin, vimentin, and snail as well as upregulation of E-cadherin. Because expressions of the angiogenic markers factor VIII and retic were downregulated, an anti-angiogenic role of WA is suggested. Overall, our results suggest that WA could be a promising anti-cancer agent that effectively inhibits carcinogenesis of the prostate.

Activation of AKT negatively regulates the pro-apoptotic function of death-associated protein kinase 3 (DAPK3) in prostate cancer

Highlights • This is the first study that demonstrates the inverse correlation of AKT activation and down-regulation of tumor suppressor protein, DAPK-3, in CaP cell lines as well as human prostate tumor tissues that correlate with disease progression.• Either silencing AKT or overexpressing DAPK-3 induces apoptosis in Castration Resistant Prostate Cancer cells.

miR-301a expression: A prognostic marker for prostate cancer.

PURPOSE The diagnosis and treatment of prostate cancer (CaP) continues to be challenging, as prostate-specific antigen (PSA) appears to be overly sensitive and biopsy is the only reliable method for confirmation. Hence, the goal of the study is to identify a biomarker that could distinguish malignant cancer from benign prostatic hyperplasia (BPH) during the early diagnosis of the disease. MATERIALS AND METHODS A total of 75 formalin fixed paraffin embedded (FFPE) with matching controls, 4 paired metastatic tumors, 6 fresh tumor tissues and BPH (13 cases) with their clinical diagnosis were selected for this study. Prostate cancer cell lines and normal prostate epithelial cell lines were obtained from ATCC and subjected to phenotypic analysis. RESULTS We observed significant differential expression of miR-301a in CaP samples in comparison to BPH and adjacent benign samples. The overexpression of miR-301a activates the invasion/migration of CaP cells. In contrast, silencing miR-301a expression inhibited the colony-forming ability, adhesion, invasion and migration of CaP cells. Similarly, the overexpression of miR-301a increased cell motility in normal RWPE-1 prostate epithelial cells. Our results suggest that miR-301a is differentially expressed between BPH and CaP specimens and that the expression of miR-301a correlates with biochemical recurrence and/or metastasis in CaP patients. CONCLUSIONS The expression of miR-301a could be a potential marker for metastasis in CaP patients. Detecting miR-301a expression during diagnosis will avoid wait and watch timelines, thus preventing morbidity.

Targeting aberrant expression of Notch-1 in ALDH+ cancer stem cells in breast cancer†

We have previously reported that high aldehyde dehydrogenase (ALDH) enzyme activity in breast cancer cells results in breast cancer stem cell (BCSC) properties by upregualting Notch‐1 and epithelial mesenchymal markers. This results in chemoresistance in breast cancer. Here, we examined the functional and clinical significance of ALDH expression by measuring the ALDH levels in breast cancer tissues by immunohistochemistry. There was a significantly higher ALDH expression in higher grade breast cancer tumor tissues (Grade‐ II and III) versus normal breast tissues. Injection of BCSC (ALDH+ and CD44+/CD22−) cells resulted in aggressive tumor growth in athymic mice versus ALDH− cells. The ALDH+ and CD44+/CD22− tumors grow rapidly and are larger than ALDH− tumors which were slow growing and smaller. Molecularly, ALDH+ tumors expressed higher expression of Notch‐1 and EMT markers than ALDH− tumors. Oral administration of the naturally occurring Psoralidin (Pso, 25 mg/kg of body weight) significantly inhibited the growth in ALDH+ and ALDH− tumors as well. Psoralidin inhibited Notch‐1 mediated EMT activation in ALDH+ and ALDH− tumors‐this confirms our in vitro findings. Our results suggest that Notch‐1 could be an attractive target and inhibition of Notch‐1 by Psoralidin may prevent pathogenesis of breast cancer as well as metastasis.

Presentation of renal cell carcinoma as cervical polyp metastasis.

Secondary cervical adenocarcinomas are most commonly seen owing to the extension of a primary endometrial adenocarcinoma. Metastatic tumors from other sites are rather uncommon and, when seen, are most frequently from the ovaries, gastrointestinal tract, or breast. We report a case of metastatic renal cell carcinoma, clear cell variant, to the cervix, which presented as a cervical polyp in a postmenopausal female. To our knowledge, this is the fourth reported case of renal cell carcinoma metastatic to the cervix. This case is only the third in which the cervical metastasis was the presenting sign of renal cell carcinoma and the first in which the clinical presentation was as a cervical polyp.

Signet Ring Cell Carcinoma of the Gallbladder in a 22-Year-Old Man: A Case Report and Review of the Literature

Primary carcinoma of the gallbladder is an uncommon malignancy with a variable incidence among different geographic locales and ethnic groups. Women are affected generally 3 times as often as men. Choleliths are a significant risk factor. Other risk factors include abnormal union of the choledochopancreatic ducts, obesity, multiparity, chronic infection with certain bacteria, and genetics. The signet ring cell subtype of adenocarcinoma is a rare entity. The behavior of this subtype is not well described in the literature. The authors present a case of signet ring cell carcinoma of the gallbladder, unusual in their case because of the patient’s young age, male gender, African American ethnicity, and lack of choleliths or any other risk factors. They review the literature in English to characterize this rare subtype.