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PubMed | Schrodinger, University of Macau, The Gujarat Cancer & Research Institute and Saurashtra University
Type: Journal Article | Journal: Journal of biomolecular structure & dynamics | Year: 2016

Transient interactions between cancer stem cells and components of the tumor microenvironment initiate various signaling pathways crucial for carcinogenesis. Predominant hyaluronan (HA) receptor, CD44 is structurally and functionally one of the most variable cell surface receptors having the potential to generate a diverse repertory of CD44 isoforms by alternative splicing of variant exons and post-translational modifications. A structurally distinctive variant of CD44, CD44v10, has an inevitable role in malignant progression, invasion, and metastasis. This can be attributed to the binding of HA with CD44v10, which demonstrates a completely different behavioral pattern as compared to the other spliced variants of CD44 molecule. Absence of a comprehensively predicted crystal structure of human CD44s and CD44v10 is an impediment in understanding the resultant structural alterations caused by the binding of HA. Thus, in this study, we aim to predict the CD44s and CD44v10 structures to their closest native confirmation and study the HA binding-induced structural perturbations using homology modeling, molecular docking, and MD simulation approach. The results depicted that modeled 3D structures of CD44s and CD44v10 isoforms were found to be stable throughout MD simulations; however, a substantial decrease was observed in the binding affinity of HA with CD44v10 (-5.355kcal/mol) as compared to CD44s. Furthermore, loss and gain of several H-bonds and hydrophobic interactions in CD44v10-HA complex during the simulation process not only elucidated the reason for decreased binding affinity for HA but also prompted toward the plausible role of HA-induced structural perturbations in occurrence and progression of carcinogenesis.


PubMed | M. S. University of Baroda and The Gujarat Cancer & Research Institute
Type: Journal Article | Journal: Pathology oncology research : POR | Year: 2016

Tumorigenesis and metastasis are frequently associated with altered structure and expression of oligosaccharides on cell surface glycoproteins and glycolipids. The expression of sialylated glycoconjugates has been shown to change during development, differentiation, disease and oncogenic transformation. Abnormal sialylation in cancer cell is a distinctive feature associated with malignant properties including invasiveness and metastatic potential. The alterations in sialylation is accompanied by changes in sialic acid, sialidase activity, sialyltransferase (ST) activity or sialoproteins. The present review summarizes the reports on alterations of sialic acid, linkage specific STs and sialoproteins, sialidase activity together with different subtypes of ST and sialidases mRNA expressions in various cancers like lung, breast, oral, cervical, ovarian, pancreatic etc. Sialic acids are widely distributed in nature as terminal sugars of oligosaccharides attached to proteins or lipids. The increase shedding of sialic acid observed in malignant tumors may be due to different types of sialidases. The amount of sialic acid is governed by levels of sialidases and STs. Various types of STs are also involved in formation of different types sialylated tumor associated carbohydrate antigens which plays important role in metastasis. The alterations associated with sialylation aids in early diagnosis, prognosis and post treatment monitoring in various cancers. Recently newer drugs targeting different interplays of sialylation have been developed, which might have profound effect in inhibiting sialylation and thus cancer metastasis and infiltration.


PubMed | Gujarat University and The Gujarat Cancer & Research Institute
Type: | Journal: Oral oncology | Year: 2016

Circulating tumor cells (CTCs) are increasingly gaining importance due to their immense potential in enhancing diagnosis, prognosis and response to therapy in solid malignancies. Therefore, we aimed to comprehend the molecular diversity and critical role of this disseminated tumor population in OSCC.CD44+ subpopulation was isolated using immuno-magnetic cell separation and their purity was validated using flow cytometry. Characterisation of self renewal potential and resistance to chemotherapy was assessed using tumor sphere forming and cytotoxicity assay. Gene expression profile of pertinent CSC (CD44s, CD44v3, CD44v6) and stemness markers (Bmi1 and Nanog) was carried out in CD44+ cells using Real Time PCR. Predominantly expressed markers and their association with clinico-pathological conditions were substantiated in 30 OSCC patients.Flow cytometry analysis depicted a predominant population of CD44+CD24-CD45- cells suggesting that circulating tumor cells had a subpopulation of CSC like cells in the circulation. These cells demonstrated increased sphere forming capability and intrinsic chemo-resistance compared to non-CSC, thus indicating the CSC features of self-renewal and chemo-resistance. Additionally, CD44+ cells showed significantly increased expression levels of CD44v6 and Nanog compared to CD44- cells. Clinically, expression pattern of CD44v6 and Nanog correlated with different anatomical subsites, loco-regional aggressiveness of the disease and recurrence, thus opening newer avenues that can be explored for better prognostic and therapeutic implications.This study explored the inevitable role of CD44v6 and Nanog as circulating stem like cell markers in assessment of loco-regional aggressiveness, detection of relapse and therapeutic response and resistance.


Raval A.,The Gujarat Cancer & Research Institute | Trivedi S.,Institute of Human Genetics
Indian Journal of Experimental Biology | Year: 2016

Deregulation of Insulin like growth factors (IGF) is an important determinant of breast carcinogenesis. Circulatory IGF-1 (potent breast mitogen) and IGFBP-3 (its regulator) are extensively evaluated; few studies report transcript copy numbers (CN) from ex-vivo samples. This study from 106 patients evaluated mRNA expression (qRT-PCR CN) of IGF-1 and IGFBP-3 for prognostic and predictive utility from tumor, adjacent normal tissues (ANT) and lymph nodes. The differences in IGF-1 and IGFBP-3 mRNA levels (CN/μg RNA) were juxtaposed to clinical and pathologic variables and survival. Tumors expressed lower IGF-1 and higher IGFBP-3 as compared to ANT. Both transcript levels decreased with increasing age. Primary tumors with nodal involvement, Invasive Lobular carcinoma (ILC) histology and stromal involvement showed increased transcript levels than their respective counterparts. Moreover, surviving patients showing no relapse had higher expression of both molecules. Early stage and necrosed tumors expressed higher IGFBP-3 while a trend of lower expression was seen as tumor grade advanced. IGF-1 expression was inversely correlated to stage, histologic grade and. Significantly different Relapse Free Survival (RFS) was seen with IGFBP-3 up-/down-regulation considering progesterone receptor (PR) status but not estrogen receptor (ER) and HER-2 while the Overall Survival (OS) was similar for both these molecules. We conclude that expression of these molecules may aid prognostication and success of anti IGF-1 strategies. © 2016, National Institute of Science Communication. All rights reserved.


Patel F.M.,The Gujarat Cancer & Research Institute | Goswami P.N.,The Gujarat Cancer & Research Institute
Indian Journal of Medical Research | Year: 2016

Background & objectives: Hepatitis delta virus (HDV) and hepatitis B virus (HBV) co-infection is well known to induce a spectrum of acute and chronic liver diseases. There has been global decline in the prevalence of hepatitis D infection. The aim of the present study was to know the presence of acute HDV infection among hepatitis B surface antigen (HBsAg) positive cancer patients. Methods: A total of 5043 samples were subjected for routine testing of HBV, HIV and HCV by ELISA method. Further, 150 HbsAg positive samples were tested for HDV IgM detection by ELISA method. Results: Of the 5043 blood samples tested in the laboratory, 150 (2.97%) were positive for HBsAg. HDV IgM was negative in all HbsAg positive samples. Interpretation & conclusions: Acute infection by HDV (IgM detection) was not present in HBsAg positive cancer patients. Further studies on a large number of patients in different regions are required to confirm our preliminary findings. © 2016, Indian Council of Medical Research. All rights reserved.


Patel S.,The Gujarat Cancer & Research Institute | Rawal R.,The Gujarat Cancer & Research Institute
Tumor Biology | Year: 2016

Late diagnosis, low therapeutic response, and metastasis are accountable for poor 5-year survival rate of OSCC. These failures are attributed to the existence of “cancer stem cell (CSC)” subpopulation. Hence, it is necessary to identify and understand the mechanism of CSCs in tumor development, metastasis, and chemotherapeutic response. Propelling evidences suggest that microRNA (miRNA)-mediated regulation and cytokines of tumor microenvironment have the ability to modulate CSC signalling pathway; however, their exact mechanism needs to be elucidated. Thus, in this study, we characterized CSC markers and highlighted the miRNA dynamics and cytokine profile regulating these CSCs in a pathway-dependent manner. Our results demonstrated CD44+ subpopulation as tumor-initiating cells with self-renewal capability, tumorigenic growth potential and intrinsic chemoresistance. These tumors exhibited increased expression of CSC markers (CD44v3, CD44v6, Nanog, and Bmi1) and significantly reduced expression of PTEN and ATM in OSCC patients. Pathway analysis of these CSC markers demonstrated a prospective pathway regulated by miRNA and cytokine network. On analyzing these modulators, we observed decreased expression of miRNA542-3p, miRNA34a and miRNA9, and significant upregulation of miRNA21, thus forming an unexplored axis. Cytokine profiling revealed significantly increased levels of IL-6 and IL-8 compared to normals and demonstrated their strong association with CD44v6. Collectively, this study indicates that miR5423p and miR34a targets the CD44v6-Nanog-PTEN axis, thus playing a vital role in regulating the CSC properties. Furthermore, we speculate an impinging role of cytokines IL-6 and IL-8 in regulating this CSC-mediated pathway which can have prognostic and therapeutic implications. © 2016 International Society of Oncology and BioMarkers (ISOBM)


PubMed | The Gujarat Cancer & Research Institute
Type: | Journal: Journal of thyroid research | Year: 2016

Circulating levels of TNF- and the adhesion molecules L-Selectin and VCAM-1 as well as their expression in the primary tumors of patients with benign thyroid diseases and papillary thyroid carcinoma (PTC) have been determined in this study. The serum levels of TNF-, L-Selectin, and VCAM-1 were significantly higher in patients with both benign thyroid diseases and PTC as compared to the healthy individuals. However, the levels of only TNF- and L-Selectin, and not VCAM-1, were significantly higher in patients with PTC in comparison to those observed in patients with benign thyroid diseases. Further the expression of TNF- and L-Selectin was also significantly higher in the primary tumors of PTC patients, relative to the benign thyroid diseases. The expression of L-Selectin and VCAM-1 significantly correlated with aggressive tumor behavior. In PTC patients, the circulating TNF- levels significantly positively correlated with the levels of L-Selectin, while TNF- immunoreactivity was significantly associated with VCAM-1 expression. Serum TNF- was found to be a significant prognosticator for OS in PTC patients. Overall the results signify that the interaction between TNF- and the adhesion molecules may have a role in thyroid carcinogenesis and understanding this complexity may offer potential therapeutic targets for better management of thyroid cancer.


PubMed | The Gujarat Cancer & Research Institute
Type: Journal Article | Journal: Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine | Year: 2016

Late diagnosis, low therapeutic response, and metastasis are accountable for poor 5-year survival rate of OSCC. These failures are attributed to the existence of cancer stem cell (CSC) subpopulation. Hence, it is necessary to identify and understand the mechanism of CSCs in tumor development, metastasis, and chemotherapeutic response. Propelling evidences suggest that microRNA (miRNA)-mediated regulation and cytokines of tumor microenvironment have the ability to modulate CSC signalling pathway; however, their exact mechanism needs to be elucidated. Thus, in this study, we characterized CSC markers and highlighted the miRNA dynamics and cytokine profile regulating these CSCs in a pathway-dependent manner. Our results demonstrated CD44+ subpopulation as tumor-initiating cells with self-renewal capability, tumorigenic growth potential and intrinsic chemoresistance. These tumors exhibited increased expression of CSC markers (CD44v3, CD44v6, Nanog, and Bmi1) and significantly reduced expression of PTEN and ATM in OSCC patients. Pathway analysis of these CSC markers demonstrated a prospective pathway regulated by miRNA and cytokine network. On analyzing these modulators, we observed decreased expression of miRNA542-3p, miRNA34a and miRNA9, and significant upregulation of miRNA21, thus forming an unexplored axis. Cytokine profiling revealed significantly increased levels of IL-6 and IL-8 compared to normals and demonstrated their strong association with CD44v6. Collectively, this study indicates that miR5423p and miR34a targets the CD44v6-Nanog-PTEN axis, thus playing a vital role in regulating the CSC properties. Furthermore, we speculate an impinging role of cytokines IL-6 and IL-8 in regulating this CSC-mediated pathway which can have prognostic and therapeutic implications.


PubMed | The Gujarat Cancer & Research Institute
Type: | Journal: Glycoconjugate journal | Year: 2016

The hallmarks of cancer are characterized by functional capabilities that allow cancer cells to survive, proliferate and disseminate during the multistep tumorigenesis. Cancer being a cellular disease, changes in cellular glycoproteins play an important role in malignant transformation and cancer progression. The present review summarizes various studies that depicted correlation of glycosylation with tumor initiation, progression and metastasis, which are helpful in early diagnosis, disease monitoring and prognosis. The results are further strengthened by our reports, which depicted alterations in sialylation and fucosylation in different cancers. Alterations in glycosyltransferases are also involved in formation of various tumor antigens (e.g. Sialyl Lewis x) which serves as ligand for the cell adhesion molecule, selectin which is involved in adhesion of cancer cells to vascular endothelium and thus contributes to hematogenous metastasis. Increased glycosylation accompanied by alterations in glycosyltranferases, glycosidases, glycans and mucins (MUC)s are also involved in loss of E-cadherin, a key molecule implicated in metastatic dissemination of cells. The present review also summarizes the correlation of glycosylation with all the hallmarks of cancer. The enormous progress in the design of novel inhibitors of pathway intermediates of sialylation and fucosylation can prove wonders in combating the dreadful disease. The results provide the evidence that altered glycosylation is linked to tumor initiation, progression and metastasis. Hence, it can be considered as a new hallmark of cancer development and strategies to develop novel glycosylation targeted molecules should be strengthened.


PubMed | The Gujarat Cancer & Research Institute
Type: | Journal: Mutation research | Year: 2016

p53 mutations are critical players in etiopathogenesis of oral cancer. Interestingly, they show differences in terms of type and codon specificity. These differences might be attributed to geographical variations in tobacco use. We aimed to analyze the frequency of p53 mutations in oral cancer patients from Gujarat, India and their effect on clinico-pathological features, local recurrence and survival.p53 mutation analysis was performed on 46 paired tissue samples (adjacent normal and primary malignant) using PCR-SSCP and sequencing.Sequencing confirmed 51 p53 mutations in 46 paired tissues. Three novel mutations (frameshift deletion in exon 4; G>T transversion at codon 117 in exon 4 and G>A transition at codon 319 in exon 9) were identified. Distinct pattern of p53 mutations was observed: more common C>T transitions and recurring mutation sites at codon 90 and 116 in exon 4. Interestingly, the probability of developing recurrence was higher in small tumors (<4 cm) with p53 mutations and in cases with p53 mutations in both adjacent normal and malignant tissues. A significant low disease free survival and overall survival was observed in cases harboring truncating and transcriptionally non-active mutations.We report a very high frequency and a diverse pattern of p53 mutations in cases from this region. Interestingly, three distinct novel mutations in exons 4 and 9 were also observed. Analyzing p53 mutation status in tumor tissues at an early stage could serve as an important prognostic factor.

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