Establishment of CML mouse model to examine the interactive role of normal hematopoietic system on the pathophysiology

The 3rd International Symposium on Carcinogenic Spiral & International Symposium on Tumor Biology in Kanazawa, [DATE]: January 24(Thu)-25(Fri),2013, [Place]:Kanazawa Excel Hotel Tpkyu, Kanazawa, Japan, [Organizers]:Infection/Inflammation-Assisted Acceleration of the Carcinogenic Spiral and its Alteration through Vector Conversion of the Host Response to Tumors / Scientific Research on Innovative Areas, a MEXT Grant-in Aid Projec

Chemokines in tumor development and progression

Chemokines were originally identified as mediators of the inflammatory process and regulators of leukocyte trafficking. Subsequent studies revealed their essential roles in leukocyte physiology and pathology. Moreover, chemokines have profound effects on other types of cells associated with the inflammatory response, such as endothelial cells and fibroblasts. Thus, chemokines are crucial for cancer-related inflammation, which can promote tumor development and progression. Increasing evidence points to the vital effects of several chemokines on the proliferative and invasive properties of tumor cells. The wide range of activities of chemokines in tumorigenesis highlights their roles in tumor development and progression. © 2011 Elsevier Inc. All rights reserved

Gemcitabine induces cell senescence in human pancreatic cancer cell lines

Patients with pancreatic ductal adenocarcinoma (PDAC) commonly require chemotherapy because they frequently develop metastatic disease or locally advanced tumors. Gemcitabine, an analogue of cytosine arabinoside, is commonly used for PDAC treatment. We observed that gemcitabine induced senescence phenotypes characterized by enhanced senescence-associated β-galactosidase (SA β-Gal) staining and increased expression of senescence-associated molecules in two human pancreatic cancer cell lines, Miapaca-2 and Panc-1, which exhibit resistance to gemcitabine but not L3.pl cells with a high sensitivity to gemcitabine. Gemcitabine-induced cell senescence can be inhibited by reactive oxygen species inhibitor, N-acetyl cysteine. Although gemcitabine also enhanced CXCL8 expression, anti-CXCL8 antibody failed to reduce gemcitabine-induced increases in SA β-Gal-positive cell numbers. These observations would indicate that cell senescence can proceed independently of CXCL8 expression, a characteristic feature of senescence-associated secretion phenotype. © 2016 Elsevier Inc.Embargo Priod 12 month

Safety and efficacy of pirfenidone in idiopathic pulmonary fibrosis in clinical practice

SummaryBackgroudPrevious pirfenidone trials have only involved patients with mild-to-moderate idiopathic pulmonary fibrosis (IPF). The aim of this study was to investigate the safety and efficacy of pirfenidone in patients with mild-to-severe IPF in clinical practice.MethodsThe clinical records of 76 patients who were diagnosed with IPF and received pirfenidone were reviewed.ResultsThe most frequent adverse event was anorexia, although the grade of anorexia in most patients was mild. Dose reduction of pirfenidone improved anorexia in 84% affected patients, which resulted in a high medication compliance rate. The mean forced vital capacity (FVC) at the initiation of pirfenidone therapy in this study was approximately 10% lower than that in previous clinical trials. The mean change in FVC during the 6-month period prior to the therapy initiation was −188 mL, which improved to −19 mL during the 6-month period after therapy. Significant attenuation in percentage predicted diffusion capacity of the lung for carbon monoxide decline was also achieved after pirfenidone therapy initiation. The efficacy of pirfenidone in attenuating the degree of FVC decline was higher in the group with FVC decline of ≥150 mL during the 6-month period prior to therapy initiation. The levels of serum markers, such as KL-6 and SP-D, were also lowered by the therapy.ConclusionsThese results showed that pirfenidone was well-tolerated and had beneficial effects in patients with mild-to-severe and/or progressive IPF. The degree of disease progression prior to the initiation of pirfenidone therapy had an impact on the response to the therapy

Tumor Immunotherapy by Utilizing a Double-Edged Sword, Chemokines

Both innate and adaptive immune responses have an essential role in protection against tumor cells. Various types of immune cells such as dendritic cells and lymphocytes contribute to the establishment of immune responses to tumor cells. Chemokines, a family consisting of more than 40 related chemoattractant proteins, have a crucial role in the control of the recruitment of immune cells needed for the induction and activation of tumor immunity. Based on these properties, several chemokines have been utilized in preclinical models to augment tumor immunity by enhancing the migration and activation of immune cells. Paradoxically, tumor tissues use chemokines to evade immunosurveillance by attracting immune suppressive cells. Moreover, chemokines can mediate survival and migration of tumor cells and promote new blood vessel formation, thereby leading to tumor progression and metastasis. Thus, a number of therapeutic strategies have been proposed to target chemokines, in order to reduce tumor progression and metastasis, although these strategies have not yet been translated to clinical situations. Here, we will briefly summarize the preclinical results obtained by using and/or targeting chemokines to combat tumors and discuss the potential efficacy of these methods. © 2013 Springer Science+Business Media New York. All rights reserved.Book Chapte

Chemokines in cancer development and progression and their potential as targeting molecules for cancer treatment

Chemokines were initially identified as bioactive substances, which control the trafficking of inflammatory cells including granulocytes and monocytes/macrophages. Moreover, chemokines have profound impacts on other types of cells associated with inflammatory responses, such as endothelial cells and fibroblasts. These observations would implicate chemokines as master regulators in various inflammatory responses. Subsequent studies have further revealed that chemokines can regulate the movement of a wide variety of immune cells including lymphocytes, natural killer cells, and dendritic cells in both physiological and pathological conditions. These features endow chemokines with crucial roles in immune responses. Furthermore, increasing evidence points to the vital effects of several chemokines on the proliferative and invasive properties of cancer cells. It is widely acknowledged that cancer develops and progresses to invade and metastasize in continuous interaction with noncancerous cells present in cancer tissues, such as macrophages, lymphocytes, fibroblasts, and endothelial cells. The capacity of chemokines to regulate both cancerous and noncancerous cells highlights their crucial roles in cancer development and progression. Here, we will discuss the roles of chemokines in carcinogenesis and the possibility of chemokine targeting therapy for the treatment of cancer. © 2014 Naofumi Mukaida et al

Crucial involvement of the CCL3-CCR5 axis-mediated fibroblast accumulation in colitis-associated carcinogenesis in mice

Patients with inflammatory bowel diseases often develop colon carcinoma. Combined treatment of azoxymethane (AOM) and dextran sulfate sodium (DSS) recapitulates colitis-associated cancer in mice. AOM/DSS-induced tumor formation was reduced in CCL3- or its specific receptor, CCR5-deficient mice despite the presence of a massive infiltration of inflammatory cells. However, AOM/DSS-induced type I collagen-positive fibroblast accumulation in the colon was reduced in CCL3- or CCR5-deficient mice. This was associated with depressed expression of heparin-binding epidermal growth factor-like growth factor (HB-EGF), which is expressed mainly by fibroblasts. Moreover in vitro, CCL3 induced fibroblasts to proliferate and to enhance HB-EGF expression. Furthermore, CCR5 blockade reduced tumor formation together with reduced fibroblast accumulation and HB-EGF expression, even when administered after the development of multiple colon tumors. Thus, CCL3-CCR5-mediated fibroblast accumulation may be required, in addition to leukocyte infiltration, to induce full-blown colitis-associated carcinogenesis. Our studies shed light on a therapeutic potential of CCR5 antagonist for patients with colitis-associated cancer. What\u27s new? Inflammation of the bowel can lead to cancer, in some cases. By learning how one leads to the other, researchers hope to find a way to stave off this progression. Previously, it\u27s been observed that these cancers have a lot of chemokine CCL3 hanging around. In this paper, the authors replicated these colitis-induced cancers in mice and investigated what CCL3 was doing. They learned that CCL3 and its receptor, CCR5, gather up cancer-associated fibroblasts, which promote transformation and tumor growth. Leukocyte infiltration wasn\u27t enough, they found; without CCL3 and CCL5 bringing in fibroblasts, the tumor development slowed. © 2014 UICC

Novel process of intrathymic tumor-immune tolerance through CCR2-mediated recruitment of Sirpα + dendritic cells: A murine model

Immune surveillance system can detect more efficiently secretory tumor-specific antigens, which are superior as a target for cancer immunotherapy. On the contrary, immune tolerance can be induced in the thymus when a tumor antigen is massively secreted into circulation. Thus, the secretion of tumor-specific antigen may have contradictory roles in tumor immunity in a context-dependent manner. However, it remains elusive on the precise cellular mechanism of intrathymic immune tolerance against tumor antigens. We previously demonstrated that a minor thymic conventional dendritic cell (cDC) subset, CD8α -Sirpα + cDCs, but not the major subset, CD8α +Sirpα - cDCs can selectively capture blood-borne antigens and crucially contribute to the self-tolerance. In the present study, we further demonstrated that Sirpα + cDCs can capture a blood-borne antigen leaking inside the interlobular vascular-rich regions (IVRs). Blood-borne antigen selectively captured by Sirpα + cDCs can induce antigen-specific Treg generation or negative selection, depending on the immunogenicity of the presented antigen. Furthermore, CCR2 expression by thymic Sirpα + cDCs and abundant expression of its ligands, particularly, CCL2 by tumor-bearing mice prompted us to examine the function of thymic Sirpα + cDCs in tumor-bearing mice. Interestingly, tumor-bearing mice deposited CCL2 inside IVRs in the thymus. Moreover, tumor formation induced the accumulation of Sirpα + cDCs in IVRs under the control of CCR2-CCL2 axis and enhanced their capacity to take up antigens, resulting in the shift from Treg differentiation to negative selection. Finally, intrathymic negative selection similarly ensued in CCR2-competent mice once the tumor-specific antigen was secreted into bloodstream. Thus, we demonstrated that thymic Sirpα + cDCs crucially contribute to this novel process of intrathymic tumor immune tolerance. © 2012 Baba et al

Essential contribution of Ets-1 to constitutive Pim-3 expression in human pancreatic cancer cells.

金沢大学がん研究所がん病態制御We previously demonstrated that the proto-oncogene Pim-3 with serine/ threonine kinase activity was aberrantly expressed in cancer cells but not in the normal cells of the pancreas. In order to elucidate the molecular mechanism underlying aberrant Pim-3 expression in pancreatic cancer cells, we constructed luciferase expression vectors linked to 5′-flanking deletion mutants of the human Pim-3 gene and transfected human pancreatic cancer cells with the resultant vectors. The region up to -264 bp was essential for constitutive Pim-3 gene expression, and the mutation in the Ets-1 binding site (between -216 and -211 bp) reduced luciferase activities. Moreover, Ets-1 mRNA and protein were constitutively expressed together with Pim-3 in human pancreatic cancer cell lines. Chromatin immunoprecipitation assay demonstrated constitutive binding of Ets-1 to the 5′-flanking region of human Pim-3 gene between -249 and -183 bp. Pim-3 promoter activity and its protein expression were induced by transfection with wild type-Ets-1 and were reduced by transfection with dominant negative-Ets-1 or Ets-1 small-interfering RNA (siRNA). Furthermore, dominant negative-Ets-1 and Ets-1 siRNA reduced the amount of Bad phosphorylated at its Ser 112 and induced apoptosis, when they were transfected into human pancreatic cancer cells. Finally, Pim-3 cDNA transfection reversed Ets-1 siRNA-induced increase in apoptosis and decrease in Bad phosphorylation at its Ser 112. These observations would indicate that the transcription factor Ets-1 can induce aberrant Pim-3 expression and subsequently prevent apoptosis in human pancreatic cancer cells. © 2009 Japanese Cancer Association

Possible Implication of Fc γ

Leukocytes can “gnaw away” the plasma membrane of other cells. This phenomenon, called trogocytosis, occurs subsequent to cell-to-cell adhesion. Currently, two mechanisms of trogocytosis, adhesion molecule-mediated trogocytosis and Fcγ receptor-(FcγR-) mediated trogocytosis, have been identified. In our earlier study, we established an in vitro model of FcγR-mediated trogocytosis, namely, CD8 translocation model from T cells to neutrophils. By using this model, we demonstrated that the molecules transferred to neutrophils via FcγR-mediated trogocytosis were taken into the cytoplasm immediately. This result suggests that the chance of molecules transferred via FcγR-mediated trogocytosis to play a role on the cell surface could be time-limited. Thus, we consider the physiological role of FcγR-mediated trogocytosis as a means to remove antibodies (Abs) that bind with self-molecules rather than to extract molecules from other cells. This concept means that FcγR-mediated trogocytosis can be a defense mechanism to Ab-mediated autoimmune response. Moreover, the activity of FcγR-mediated trogocytosis was revealed to be parallel to the endocytotic activity of neutrophils, which was critically related to the susceptibility to systemic autoimmune diseases. The collective findings suggest that FcγR-mediated trogocytosis could physiologically play a role in removal of Abs bound to self-antigens and prevent autoimmune diseases