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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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.

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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.

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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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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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Context/Aims: Metabolic reprogramming and cellular plasticity drive tumorigenesis. However, how these cellular events collectively contribute to the oncogenic process is poorly understood. Epithelial-mesenchymal transition (EMT), a fundamental mechanism of cellular plasticity, is governed by the EMT transcription repressors such as Snail. In the present study, through establishment and characterization of inducible overexpression of Snail in A549 lung cancer cells, we aim to define the metabolic reprogramming in response to Snail in the EMT of lung cancer cells. Methods/Results: Our metabolomic analysis suggests that forced expression of Snail accompanied reduced diversion of glycolytic metabolites to the serine/glycine metabolic shunt, a critical metabolic branch that distributes glucose catabolic intermediates to the major anabolic pathways. Our gene expression profiling and molecular characterization revealed that Snail actively suppressed the expression of glycine decarboxylase (GLDC), a key enzyme on the serine/glycine metabolic shunt, through binding to an evolutionarily conserved E-box motif and thereby inhibiting the promoter of the GLDC gene. Besides, knockdown of GLDC led to a cellular function shift from proliferation to migration. Conclusion: This study has revealed a novel molecular link that integrates the serine/glycine metabolism with the Snail-mediated EMT program in cancer cells.

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The interaction between the bone marrow microenvironment and leukemia cells enhances cell adhesion-mediated signals that can promote malignant hematopoietic cell survival and change normal hematopoiesis. Integrins, on the surface of leukemia cells, are involved in this interaction and mediate cell adhesion to integrin receptors of other cells and the extracellular matrix. Studies show that inhibition of several integrins affects leukemia cell migration or survival as well as sensitivity to chemotherapy. This review focuses on the expression and role of key arginine–glycine–aspartate acid (RGD)-binding (αvβ3, α5β1, αIIbβ3) and non-RGD-binding (α2β1, α4β1, α6β1, and αLβ2) integrins on leukemia cells and in the leukemia microenvironment and their potential targeting in leukemia treatment.

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