Development and Clinical Application of Tumor-derived Exosomes in Patients with Cancer.

A tumor is an abnormal growth of cells within a tissue that can lead to death due to late diagnosis, poor prognosis, drug resistance, and finally enhanced metastasis formation. Exosomes are nanovesicles that have been derived from all the different cell types. These vesicles can transfer various molecules, including the distinct form of nucleic acids (mRNA, miRNA, and circRNA) and proteins. Tumor-derived exosomes (TEXs) have exceptionally important roles through multiple molecular and cellular pathways like progression, tumorigenesis, drug resistance, and as well as metastasis. TEXs are detectable in all body fluids such as serum and urine, a convenient and non-invasive way to access these nano-sized vesicles. TEXs lead to the symptom expression of genetic aberrations in the tumor cell population, making them an accurate and sensitive biomarker for the diagnosis and prognosis of tumors. On the other hand, TEXs contain major histocompatibility complexes (MHCs) and play important dual roles in regulating tumor immune responses: they can mediate both immune activation and suppression through tumor-associated immunity. Despite numerous scientific studies, there are still many technical barriers to distinguish TEXs from non-tumor-derived exosomes. Even so, removing exosomes leading to a wide difference in outcomes inside a patient's body. Hence, controversial pieces of evidence have demonstrated the vital role of TEXs as hopeful biomarkers for the early detection of cancers, evaluation of therapeutic effects, and monitoring of the patient.

The Role of the Curcumin for Inducing Apoptosis in Acute Lymphoblastic Leukemia Cells: A Systematic Review.

Acute lymphoblastic leukemia (ALL) is a hematological malignancy of lymphoid progenitor cells associated with excessive proliferation of lymphocytes. Curcumin, a polyphenolic compound, is known to possess anticancer activity. However, the mechanism of apoptosis induction differs in cancers. In this study, we discuss the potential apoptosis and anticancer effect of curcumin on the ALL. After choosing Medical Subject Headings (MeSH) keywords, including "Curcumin", "acute lymphoblastic leukemia", "apoptosis", as well as searching Medline/PubMed, Scopus, Sciencedirect. hand searching in key journals, list of references of selected articles and gray literature, without time and language limitation, articles up to December 2017 were entered into this review. In this review, 244 articles were acquired at the primary search. Study selection and quality assessment processes were done based on Cochrane library guidelines. According to six articles that were selected, curcumin could enhance the antitumor activity of chemotherapy drugs such as L-asparaginase. Curcumin induces apoptosis in Pre B- ALL and T- ALL cells by decreased NF-kB levels, increased p53 levels, PARP-1 cleavage. Also, the induction of growth-arrest and apoptosis in association with the blockade of constitutively active JAK-STAT pathway suggests this be a mechanism by curcumin. Curcumin could be used for the treatment of cancer like ALL.

Mesenchymal stromal cells induce inhibitory effects on hepatocellular carcinoma through various signaling pathways.

Hepatocellular carcinoma (HCC) is the most prevalent type of malignant liver disease worldwide. Molecular changes in HCC collectively contribute to Wnt/ß-catenin, as a tumor proliferative signaling pathway, toll-like receptors (TLRs), nuclear factor-kappa B (NF-κB), as well as the c-Jun NH2-terminal kinase (JNK), predominant signaling pathways linked to the release of tumor-promoting cytokines. It should also be noted that the Hippo signaling pathway plays an important role in organ size control, particularly in promoting tumorigenesis and HCC development. Nowadays, mesenchymal stromal cells (MSCs)-based therapies have been the subject of in vitro, in vivo, and clinical studies for liver such as cirrhosis, liver failure, and HCC. At present, despite the importance of basic molecular pathways of malignancies, limited information has been obtained on this background. Therefore, it can be difficult to determine the true concept of interactions between MSCs and tumor cells. What is known, these cells could migrate toward tumor sites so apply effects via paracrine interaction on HCC cells. For example, one of the inhibitory effects of MSCs is the overexpression of dickkopf-related protein 1 (DKK-1) as an important antagonist of the Wnt signaling pathway. A growing body of research challenging the therapeutic roles of MSCs through the secretion of various trophic factors in HCC. This review illustrates the complex behavior of MSCs and precisely how their inhibitory signals interface with HCC tumor cells.

Aberrant DNA Methylation in Chronic Myeloid Leukemia: Cell Fate Control, Prognosis, and Therapeutic Response.

Chronic myeloid leukemia (CML) is a hematopoietic stem cell malignancy characterized by the expression of the BCR-ABL1 fusion gene with different chimeric transcripts. Despite the crucial impact of constitutively active tyrosine kinase in CML pathogenesis, aberrant DNA methylation of certain genes plays an important role in disease progression and the development of drug resistance. This article reviews recent findings relevant to the effect of DNA methylation pattern of regulatory genes on various cellular activities such as cell proliferation and survival, as well as cell-signaling molecules in CML. These data might contribute to defining the role of aberrant DNA methylation in disease initiation and progression. However, further studies are needed on the validation of specific aberrant methylation markers regarding the prognosis and prediction of response among the CML patients.

Coexistence of p190 BCR/ABL Transcript and CALR 52-bp Deletion in Chronic Myeloid Leukemia Blast Crisis: A Case Report.

We introduce a 78-year-old woman presented with thrombocytosis and high blast count who had a history of splenectomy. Her cytogenetic analysis revealed aberrant chromosomal rearrangements in different clonal populations harboring 46XX karyotype with t(9;22) (q34;q11). RT-PCR assay detected the e1a2 BCR-ABL translocation resulting from rearrangement of the minor breakpoint cluster region (m-bcr) in BCR gene. Subsequent evaluation of the disease showed calreticulin (CALR) 52-bp deletion as well as the absence of JAK2 (V617F) heterozygous mutation in granulocyte population of peripheral blood using allele-specific PCR and bi-directional DNA sequencing. To our knowledge, this is the first case of a patient initially diagnosed as p190 BCR-ABL transcript positive CML in blast crisis characterized by a 52-bp deletion in CALR gene.

Inhibition of Ras-mediated signaling pathways in CML stem cells.

BACKGROUND: Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder characterized by the presence of the BCR-ABL1 oncoprotein in cells with a hematopoietic stem cell (HSC) origin. BCR-ABL1 tyrosine kinase activity leads to constitutive activation of Ras, which in turn acts as a branch point to initiate multiple downstream signaling pathways governing proliferation, self-renewal, differentiation and apoptosis. As aberrant regulation of these cellular processes causes transformation and disease progression particularly in advanced stages of CML, investigation of these signaling pathways may uncover new therapeutic targets for the selective eradication of CML stem cells. Transcription factors play a crucial role in unbalancing the Ras signaling network and have recently been investigated as potential modulators in this regard. In this review, we first briefly summarize the Ras-associated molecular pathways that are involved in the regulation of CML stem cell properties. Next we discuss the relevance of Ras-associated transcription factors as nuclear targets in combination treatment strategies for CML. CONCLUSIONS: A closer investigation of the influence of Ras-mediated signaling pathways on CML progression to blast crisis is warranted to uncover new directions for targeted therapies, particularly in cases that are resistant to current tyrosine kinase inhibitors.

Regulatory effect of chemokines in bone marrow niche.

Chemokines secreted from different cellular components of bone marrow (BM) play an important role in the formation of the BM niche system. The hematopoietic stem cell (HSC) pool located in specialized anatomical sites within the BM is subjected to a complex network of chemokines, such that the produced chemokines affect the fate of these cells. Expression of different chemokine receptors on leukemic stem cells (LSCs) uncovers the critical role of chemokines in the maintenance, survival and fate of these cells in the leukemic niche. As a pre-metastatic niche rich in a variety of chemokines, the BM niche is turned into a locus of tumor cell development and division. The chemokine receptors expressed on the surface of metastatic cells lead to their metastasis and homing to the BM niche. Knowledge of chemokines and their receptors leads to the production of various therapeutic antagonists at chemokine receptors expressed on leukemic and tumor cells, enabling interference with chemokine function as a therapeutic tool. New findings suggest that miRNAs, with their specific inhibitory function, affect the ability of producing and expressing chemokines and chemokine receptors. This review focuses on the emerging role of chemokines and their receptors in normal and pathologic conditions of the BM niche, and also discusses the new therapeutic methods with this background.