Faculty Bibliography

Following the publication of this article, which was concerned with the expression of phosphorylated epidermal growth factor receptor (pEGFR) and cyclin D1 activation independently of the expression levels of cyclo-oxygenase-2, an interested reader drew to our attention apparent anomalies associated with the western blot data shown in Fig. 2C. Following an internal investigation at the New York University School of Medicine, we were requested to produce the original film, or the scan of the image of the film, for verification. Unfortunately, we were unable to provide the original film or scanned image to disprove the allegation, since the original pEGFR image could not be found. Therefore, the Investigation Committee recommended that this article be retracted, and we are withdrawing the article in line with the request. All the authors agree to the retraction of this paper. We sincerely regret any inconvenience this has caused. [the original article was published in the International Journal of Oncology 40: 13-20, 2012; DOI: 10.3892/ijo.2011.1211].

Melinjo (Gnetum gnemon L.) seed extract (MSE) and its active ingredient gnetin C (GC), a resveratrol dimer, have been shown to possess a broad spectrum of pharmacological activities. In this study, we investigated the antitumor activity of MSE and GC using human and murine tumor cell culture models in vitro. The antitumor activity of GC was compared with trans-resveratrol (tRV), a stilbenoid polyphenol. Our results show that MSE and GC at clinically achievable concentrations significantly inhibited the proliferation of pancreatic, prostate, breast, and colon cancer cell types (P < 0.05), without affecting normal cells. Interestingly, GC exerts enhanced antitumor activity than that of tRV (P < 0.05). MSE and GC significantly induced apoptosis in all the cancer cells, indicating MSE and GC inhibit tumor cell growth by inducing apoptosis (P < 0.001). Our findings provide evidence that MSE might induce apoptosis in cancer cells via caspase-3/7-dependent and -independent mechanisms. However, GC might trigger both early and late stage apoptosis in cancer cells, at least in part by activating caspase 3/7-dependent mechanisms. Furthermore, the antitumor efficacy of MSE observed in vitro was also validated in a widely used colon-26 tumor-bearing mouse model. Oral administration of MSE at 50 and 100 mg/kg per day significantly inhibited tumor growth, intratumoral angiogenesis, and liver metastases in BALB/c mice bearing colon-26 tumors (P < 0.05). In conclusion, our findings provide evidence that MSE and GC have potent antitumor activity. Most importantly, we provide the first evidence that MSE inhibits tumor growth, intratumoral angiogenesis, and liver metastasis in a colon-26 tumor-bearing mice.

Dysregulation of PI3K-AKT-mTOR pathway has been reported in various pathologies, such as cancer and insulin resistance. The proline-rich AKT substrate of 40-kDa (PRAS40), also known as AKT substrate 1 (AKT1S1), lies at the crossroads of these cascades and inhibits the activity of the mTOR complex 1 (mTORC1) kinase. This review discusses the role of PRAS40 and possible feedback mechanisms, and alterations in AKT/PRAS40/mTOR signaling that have been implicated in the pathogenesis of tumor progression. Additionally, we probed new datasets extracted from Oncomine, a cancer microarray database containing datasets derived from patient samples, to further understand the role of PRAS40 (AKT1S1). These data strongly supports the hypothesis that PRAS40 may serve as a potential therapeutic target for various cancers.

Background: Extracellular matrix (ECM) characteristics, including stiffness, geometry, chemistry, and spatial interaction with the neighboring cells and soluble factors are key components for cancer cell survival in a pathogenic tissue microenvironment (TME). However, poor performance of 2D in vitro systems and animal models for metastatic cancer types demands physiologically relevant well controlled 3D platforms to quantitatively assess (a) metastatic cancer stem cell survival (b) oncogenic mechanisms and (c) drug resistant phenotypes and (d) new drug efficacy. Advances in the "state of the art" 3D platforms with difference in matrix stiffness and viscoelastic properties are showing promising results in identifying changes in drug resistant phenotypes, cell behavior and gene expression profiles. Preliminary findings by us and others using 3D matrices for human multiple myeloma (MM) reveal promising results on cancer /stromal cell interactions. In this study we have shown that Hyaluronic acid (HA) based 3D hydrogel support human metastatic MM cancer cells survival and thus reveal new oncogenic mechanisms of drug resistant cancer stem cells. Experimental approaches: Bone marrow derived CD138 positive cells and BMSCs were isolated from MM patient samples (with IRB approval) using magnetically labeled CD138 MicroBeads (autoMACS Pro Starting Kit). Bone marrow stromal cells (BMSCs) were cultured as described by us earlier. Cell viability measurements and quantitative RT-PCR for c-myc and other related gene targets were performed using total RNA. Me-HA-3D hydrogels were created containing either fibronectin/collagen/laminin or ME-HA mixture of Matrigel/fibronectin/laminin in different ratios. Cells were grown as surface seeded or encapsulated in Me-HA gels, and analyzed between 4 and 21 days in the conditioned medium. Cell proliferation analysis was performed by both MTS and live dead cell assays using CFSE stain. Results: The overall cell viability by surface coating and in encapsulated gel was found to be higher than 80% for up to 21 days in all the conditions including changes in the UV cross linking time and gel stiffness. Colony forming units (CFU) of the mononuclear cells were higher (27%) at 21 days compared to the 4 days 3% (p>0.001). Spheroids were found on the surface of the hydrogels with PC-3 cells as well as inside the encapsulated hydrogels specifically for MM, and were higher in numbers (>30%) compared to that in surface coating (5%) p>0.001. qRT-PCR analysis determined c-myc, cyclin D1, E-cadherin, and ZEB-1 showed>4 fold increase (p>0.001) in encapsulated cells compared to that in cells transfected with siRNA for c-myc, suggesting c-myc mediated cell survival in 3D. Summary: Me-HA hydrogels are found to be suitable platform for the first time to identify new metastatic cancer phenotypes types and to investigate drug resistance mechanisms

BACKGROUND:Emerging interest on three-dimensional (3D) cell culture models to replace two-dimensional cultures of cancer cells and their xenografts in immunocompromised animal hosts prompted us to investigate the use of new biodegradable gels to recapitulate the physiological conditions of the microenvironment of multiple myeloma (MM) cells. MATERIALS AND METHODS/METHODS:In the present study, for the first time, we used a new 3D model of hyaluronic acid (HA)-based hydrogels with difference in their matrix composition and stiffness. RESULTS:We demonstrated that hyaluronic acid (HA)-based hydrogels perfectly accommodate MM cells; confirmed by cell survival, migration, colony forming units and expression of cell adhesion proteins of the Wnt signaling pathways over a period of time. CONCLUSION/CONCLUSIONS:This study provides the first 3D microenvironment data that HA-based hydrogels could provide with a suitable 3D substratum for MM cells to comprehensively analyze phenotypic changes and the influence of bone marrow stromal stem cells on Wnt/β catenin signaling in response to targeted drug treatments.

Pancreatic cancer is the most common cancer among men and women; the fourth leading cause of cancer death in the United States and the fifth leading cause of cancer death worldwide. This disease has a poor prognosis with a 5-year overall survival rate of less than 20%. Multiple mechanisms have been postulated for the development of benign and malignant pancreatic diseases. However, the nature and origin of the precursor cells for pancreatic cancer have not yet been delineated. Based on several molecular mechanism(s) proposed for pancreatic cancer, the phosphoinositide 3-kinase (PI3K)/Akt pathway is found to be constitutively activated and the mammalian target of rapamycin (mTOR) kinase is reported to be an important mediator for its signaling. The phosphoinositide 3-kinase-AKT-mammalian target of rapamycin (PI3K-AKT-mTOR) pathway is a frequently hyper activated pathway in cancer and is important for tumor cell growth and survival. The development of targeted therapies against mTOR pathway led to the approval of drugs including everolimus and temsirolimus, for the treatment pancreatic and other cancer types. However, the effectiveness and response among high risk patients still remains unclear. Epidemiologic and laboratory studies suggest that plant-derived bioactive food components reverse or prevent the development and progression of early-stage disease before it becomes aggressive and malignant. Lately, naturally occurring non-toxic dietary compounds are increasingly used as a novel strategy for the prevention of more aggressive cancers. Previous reports from our laboratory suggest that prolonged exposure of cancer cells to natural agents may effectively modulate mTOR signaling and promote anti-proliferative effects. In the present study, we evaluated the effectiveness of celastrol in human (AsPC-1) and mouse (Pan-02) pancreatic cancer cells. Celastrol is a plant extract isolated from the root extract of Tripterygium Wilfordi (Thunder of God vine -TGV) and Celastrus Regelii, is also known as !

Introduction Bone marrow stromal cells (BMSC) provide a suitable microenvironment for multiple myeloma (MM) cell survival, resistance and related osteolytic bone disease. Wnt signaling enhances osteoblast proliferation and mineralization, whereas it blocks osteoblast apoptosis and osteoclast differentiation by increasing the OPG/RANKL ratio. The Wnt inhibitor Dickkopf 1 (Dkk1) negatively regulates canonical Wnt signaling by binding to and antagonizing the Wnt co-receptors Lrp5/6 (He et al., 2004). Serum levels of DKK1 have been reported to be elevated in patients with MM, while osteoprotegrin levels are decreased (Tian et al 2003). Crosstalk between Wnt/beta-catenin and other signaling pathways within the bone marrow microenvironment that regulate the osteogenic differentiation of mesenchymal stem cells (MSCs) has been reported previously (Cawthorne et al. 2012 and Krishnan et al. 2006). However the question of whether the pro-oncogenic effect of Wnt-beta-catenin signal from the stroma antagonizes the elevated serum DKK1 and thus actually enhance the osteolytic actvities in MM relapse remains to be answered. Methods Bone marrow-derived stromal fibroblasts from myeloma patients were maintained in culture for 21 days. Adherent stromal fibroblast (confirmed with staining for Vimentin) and non-adherent cells were examined for DKK1 by ELISA and for Wnt beta-catenin by performing (a) immunofuoresence detection, (b) luciferase reporter assays and (c) Western blot analysis. Results Adherent stromal fibroblasts showed beta-catenin expression after 21 days in culture (Fig 1), the signal for beta-catenin expression was 68% compared to that in non-adherent BM cells (27%). Consistently, luciferase reporter assays of adherent stromal fibroblasts transfected with Wnt/beta-cat responsive reporter plasmids (STF16) showed >4 fold increase in the reporter activity compared to that in the MM cells. As expected, the level of soluble DKK1 was significantly lower in patients with early MM (ranges from 5167 +/- 379 pg!