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REVIEW ARTICLES
A closer look at the bone marrow microenvironment in multiple myeloma
Julie Stakiw, Mark Bosch, Hadi Goubran
January-March 2018, 1(1):1-8
DOI:10.4103/2395-7182.203049  
Multiple myeloma, a plasma cell (PC) neoplasm accounting for nearly 10% of hematologic malignancies, remains an incurable disease of the bone marrow (BM) with a fascinating pathophysiology. The maladaptive nature of myeloma PCs and the BM microenvironment niche has been recognized to play a crucial role in the pathogenesis and progression of the disease which behaves in a manner similar to solid tumors in their growth and dissemination. A complex interaction between osteoclasts, endothelial cells, BM matrix, myeloid as well as the lymphoid elements and the malignant PCs occurs at the level of the microenvironment favoring the expansion of latter cells and their spread. A better understanding of the diseased PC and their milieu will enable the development of novel therapeutic tools capable of improving the outcome of this incurable blood cancer.
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ORIGINAL ARTICLES
Significance of phosphorylated epidermal growth factor receptor, matrix metalloproteinases, and E-cadherin in oral cancer
Bhairavi N Vajaria, Kinjal R Patel, Rasheedunnisa Begum, Jayendra B Patel, Franky D Shah, Prabhudas S Patel
January-March 2018, 1(1):16-24
DOI:10.4103/2395-7182.203050  
Objective: The most challenging problem in oral cancer is late monitoring and disease spread (metastasis). The study aimed to simultaneously evaluate phosphorylated epidermal growth factor receptor (pEGFR), truncated E-cadherin protein, and matrix metalloproteinases (MMPs) in patients with oral cancer. Methodology: pEGFR and truncated E-cadherin protein were measured from 25 paired tissues by ELISA and Western blot, respectively. Plasma MMPs levels were studied by gelatin zymography from 100 controls and 100 patients with oral cancer. The results revealed significant higher expression of pEGFR and truncated E-cadherin protein in malignant oral cancer tissues as compared to adjacent normal. Plasma MMPs were significantly elevated in patients with oral cancer as compared to the controls. An increase in the levels of pEGFR and truncated E-cadherin protein was observed in advanced and metastatic disease as compared to early and nonmetastatic disease. The levels of MMPs were increased in advanced disease as compared to early disease. Kaplan–Meier's survival analysis indicated that elevated expression of pEGFR, truncated E-cadherin protein, active MMP-2, pro MMP-9, total MMP-2, and total MMP-9 has reduced the overall survival. Conclusion: Simultaneous elevation of pEGFR, truncated E-cadherin protein, and MMPs indicated its role in oral carcinogenesis. Further combination therapies targeting these markers might help in combating oral cancer.
  1,413 259 -
REVIEW ARTICLES
Ursolic acid and quercetin: Promising anticancer phytochemicals with antimetastatic and antiangiogenic potential
Dharambir Kashyap, Hardeep Singh Tuli, Vivek Kumar Garg, Suhasini Bhatnagar, Anil K Sharma
January-March 2018, 1(1):9-15
DOI:10.4103/tme.tme_3_17  
Despite available treatments, the incidence of the cancer is increasing and known to be a major cause of mortality worldwide. Plant-derived terpenoids and flavonoids are considered as promising therapeutic molecules, possessing a range of medicinal properties. These phytochemicals have been used as therapeutic agents for the treatment of the various chronic infections. Terpenoids and flavonoids, particularly ursolic acid (UA) and quercetin (Quer), respectively, are emerging as effective antitumor molecules with minimal cytotoxic effects on the normal body tissues. The regulatory role of these molecules in apoptosis, angiogenesis, invasion, or metastasis has been well documented in earlier studies. Angiogenesis and metastasis are the two important hallmarks for the survival of tumor and are responsible for 50% mortality in the cancer patients. Tumor angiogenesis and metastasis have been found to be significantly inhibited in the presence of UA and Quer. Evidence suggested that these phytochemicals inhibit the initiator and progressive cytokines, chemokines, and growth factors such as matrix metalloproteinases involved in extracellular matrix remodeling during tumor metastasis. In addition, the angiogenesis-associated factors such as hypoxia-inducible factor-α and vascular endothelial growth factor/vascular endothelial growth factor receptor have also been downregulated by UA and Quer. In the present review, molecular targets of UA and Quer, in tumor metastasis and angiogenesis, have been summarized.
  1,357 261 2
ORIGINAL ARTICLES
Treatment with Src inhibitor dasatinib results in elevated metastatic potential in the 4T1 murine mammary carcinoma model
Veronica S Hughes, Dietmar W Siemann
January-March 2018, 1(1):30-36
DOI:10.4103/tme.tme_19_17  
Introduction: The src inhibitor dasatinib has been widely studied as an antimetastatic agent. The aims of this study were to examine the effect of Src inhibition on the metastatic potential of the 4T1 murine mammary carcinoma. Context: Src is a nonreceptor tyrosine kinase well known to contribute to the metastatic potential of tumor cells. It does so through alteration of signaling pathways important to metastasis. Elevated levels of Src are common in many cancer types and have been correlated with tumor progression and poor patient prognosis. Aims: This study examined whether disruption of the Src signaling pathway could inhibit metastasis formation. Settings and Design: The Src inhibitor dasatinib was evaluated in vitro and in vivo using the highly metastatic 4T1 murine mammary adenocarcinoma cell line. Methods: In vitro assays included growth curve, Western blot, migration, and invasion assays. In vivo assays included intradermal and tail vein injection models. Statistical Analysis Used: In vitro data were analyzed using one-way ANOVA with Dunnett's multiple comparisons in GraphPad Prism 6.0. In vivo data were analyzed using GraphPad Prism 6.0, using the Wilcoxon matched pairs test. Results: Dasatinib is effective at inhibiting in vitro phosphorylation of Src, migration and invasion in the 4T1 cell line, as well as angiogenesis in vivo. In vitro treatment with dasatinib impaired the metastatic ability of tumor cells as assessed by a tail vein injection model. However, both the syngeneic BALB/c and the athymic nu/nu mice receiving oral doses of the drug developed significantly higher numbers of 4T1 lung metastases. This effect was neither seen in a different breast carcinoma cell line, the MDA-MB-231-4175-LM2 nor in the murine fibrosarcoma KHT cell line. Conclusions: The 4T1 cell line is not an appropriate model to study Src inhibition.
  936 167 -
Role of human epidermal growth factor receptor 2 antagonist (Trastuzumab) in the management of nonmuscle-invasive urinary bladder carcinoma
Raafat Hegazy, Abdelmonem Hegazy, Mostafa Kamel, Ola El-Farargy, Nashwa Nawar, Ahmed El-Atar
January-March 2018, 1(1):25-29
DOI:10.4103/tme.tme_15_17  
Background: Superficial bladder cancers (nonmuscle invasive) are commonly faced by urologists and represent a major challenge for urologists and oncologists, especially Grade III carcinomas, whether conservative treatment is sufficient alone or with radical cystectomy is essential. Aim of the Study: We aimed to find a way to avoid recurrences in the nonmuscle-invasive bladder cancer and in the same time avoid radical cystectomy. Patient and Methods: We selected 42 patients with nonmuscle-invasive bladder cancers from those attending to Urology Department, Zagazig University Hospitals, from December 2011 to January 2015. After complete transurethral resection (TUR) bladder resection, diagnosis of biopsy was based on H and E-stained sections. Then, human epidermal growth factor receptor 2 (Her2) immunostaining was performed for all paraffin blocks derived from the patients. Trastuzumab was given to all cases that were positive to Her2, and only one case of them did not receive trastuzumab and left as a control. All cases then underwent follow-up for 20 months. Results: We found a significant relationship (P = 0.05) between Her2 immunostaining positivity and tumor stage, grade, multifocality, and recurrences/progression. Most cases who received trastuzumab did not undergo recurrences (19/22) (P = 0.005). We found also decrease in the immunostaining in cases of recurrences, indicating the presence of other factors affecting the occurrence or recurrences/progression. Conclusions: We concluded that administration of anti-Her2 therapy (like trastuzumab) may be essential for Her2-positive superficial bladder cancer to avoid recurrences after complete TUR bladder (TURB). Recommendation: We recommend for other studies on the significances of recurrences and how to avoid them.
  672 135 -
REVIEW ARTICLES
Aberrant expression of p14ARF in human cancers: a new biomarker?
Kazushi Inoue, Elizabeth A Fry
0, 0(0):0-0
DOI:10.4103/tme.tme_24_17  
The ARF and INK4a genes are located on the same CDKN2a locus, both showing its tumor-suppressive activity. ARF has been shown to monitor potentially harmful oncogenic signalings, making incipient cancer cells undergo senescence or programmed cell death to prevent cancer. On the other hand, INK4a detects both aging and incipient cancer cell signals. The efficiency of detection of oncogenic signals is more efficient for the for the former than the latter in the mouse system. Both ARF and INK4a genes are inactivated by gene deletion, promoter methylation, frameshift, aberrant splicing although point mutations for the coding region affect only the latter. Recent studies show the splicing alterations that affect only ARF or both ARF and INK4a genes, suggesting that ARF is inactivated in human tumors more frequently than what was previously thought. The ARF gene is activated by E2Fs and Dmp1 transcription factors while it is repressed by Bmi1, Tbx2/3, Twist1, and Pokemon nuclear proteins. It is also regulated at protein levels by Arf ubiquitin ligase named ULF, MKRN1, and Siva1. The prognostic value of ARF overexpression is controversial since it is induced in early-stage cancer cells to eliminate premalignant cells (better prognosis); however, it may also indicate that the tumor cells have mutant p53 associated with worse prognosis. The ARF tumor suppressive protein can be used as a biomarker to detect early-stage cancer cells as well as advanced stage tumors with p53 inactivation.
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ORIGINAL ARTICLES
Commonly expressed genes among cancer stem cells induced from hiPSCs and obtained from cancer tissues or cell lines
Akimasa Seno, Masaharu Seno
0, 0(0):0-0
DOI:10.4103/tme.tme_1_18  
Introduction: Cancer is one of the serious health problems in worldwide. For the development of radical cancer treatment, cancer stem cells (CSCs) are getting an issue of focus. CSCs are thought to be resistant to chemotherapy and cause metastasis. Although it is very important to understand their characters in detail, the knowledge so far is not sufficient due to their low ratio in tumor tissues. Subjects and Methods: We have induced CSCs from induced pluripotent stem cells (iPSCs) culturing in the conditioned media from cancer-derived cells without introducing genes or mutations. These induced CSCs actually have CSCs-like properties of self-renewal, differentiation potential, and tumorigenicity. In this study, their gene expression data are compared with more than 1000 sets of data from normal stem cells, our CSCs, CSCs obtained from cancer tissues or cell lines and cancer cells, which obtained from Gene Expression Omnibus. Results: Although there were no known cancer stem cell markers which can distinguish CSCs from other cell types, clustering with spherical self-organizing map revealed the expression of NTNG1, ABLIM2, DNM3, EDN1, XLOC_001990, and ISY1-RAB43 are significantly high in CSCs. Conclusion: Their expression should help to find CSCs as the markers in the future. Simultaneously, the function of these genes should become important to be clarified.
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