Changes in cytokine production and morphology of murine lymphoma NK/Ly cells in course of tumor development

2007 ◽  
Vol 2 (1) ◽  
pp. 71-86 ◽  
Author(s):  
Rostyslav Panchuk ◽  
Natalia Boiko ◽  
Maxim Lootsik ◽  
Rostyslav Stoika
Keyword(s):  
Tumor Growth ◽  
Tumor Cells ◽  
Ascitic Fluid ◽  
Tumor Development ◽  
Pcr Analysis ◽  
Vegf Mrna ◽  
Lymphoma Cells ◽  
Extracellular Medium ◽  
Enhanced Production ◽  
Ifn Γ

AbstractThe main goal of this study was to evaluate if specific cytokine expression in the NK/Ly lymphoma cells might be involved in development of intoxication in the tumor-bearing animals. RT-PCR analysis was used to study an expression of mRNA coding for IL-1α, IL-6, TNF-α, TNF-β and VEGF. ELISA was used to evaluate IL-6 and IFN-γ concentration in the ascitic fluid. Cytomorphological investigation of tumor cells was done after standard Romanovsky-Giemsa staining, and chromatin staining was performed with hematoxyline and neutral red. Lactate dehydrogenase and acid phosphatase release from tumor cells was estimated. It was revealed that the level of mRNA coding for VEGF and IL-6 was significant in the lymphoma cells. The level of VEGF mRNA was initially high and did not change during tumor progression, while the level of expression of IL6 mRNA was low at the initial stages of tumor growth and markedly increased (up to 5-fold) at the terminal stages. The obtained data on IL-6 mRNA expression were confirmed by ELISA, which showed more than 6-fold increase (from 90 to 570 pg/ml) in the IL-6 concentration in the ascitic fluid at late stages of NK/Ly tumor development. On the contrary to IL-6, concentration of IFN-γ in the ascitic fluid was very high at early stages of tumor development (1,000 pg/ml) and it markedly decreased (up to 30-fold, 30 pg/ml) at the terminal stages of tumor development. The high levels of IL-6 mRNA in tumor cells and IL-6 content in extracellular medium correlated with cell deterioration, as revealed by cytomorphologic study and the release of intracellular enzymes into extracellular medium. We suggest that an enhanced production and release of IL-6 by lymphoma cells can cause intoxication and exhaustion of the organism observed at terminal stages of tumor growth.

scholarly journals Strategies to Interfere with Tumor Metabolism through the Interplay of Innate and Adaptive Immunity

Cells ◽  
2019 ◽  
Vol 8 (5) ◽  
pp. 445 ◽  
Author(s):  
Javier Mora ◽  
Christina Mertens ◽  
Julia K. Meier ◽  
Dominik C. Fuhrmann ◽  
Bernhard Brüne ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Tumor Cells ◽  
Immune Cells ◽  
Tumor Development ◽  
Metabolic Activation ◽  
Growth And Survival ◽  
Metabolic Characteristics ◽  
Inflammatory Phenotype ◽  
Tumor Outgrowth

The inflammatory tumor microenvironment is an important regulator of carcinogenesis. Tumor-infiltrating immune cells promote each step of tumor development, exerting crucial functions from initiation, early neovascularization, to metastasis. During tumor outgrowth, tumor-associated immune cells, including myeloid cells and lymphocytes, acquire a tumor-supportive, anti-inflammatory phenotype due to their interaction with tumor cells. Microenvironmental cues such as inflammation and hypoxia are mainly responsible for creating a tumor-supportive niche. Moreover, it is becoming apparent that the availability of iron within the tumor not only affects tumor growth and survival, but also the polarization of infiltrating immune cells. The interaction of tumor cells and infiltrating immune cells is multifaceted and complex, finally leading to different activation phenotypes of infiltrating immune cells regarding their functional heterogeneity and plasticity. In recent years, it was discovered that these phenotypes are mainly implicated in defining tumor outcome. Here, we discuss the role of the metabolic activation of both tumor cells and infiltrating immune cells in order to adapt their metabolism during tumor growth. Additionally, we address the role of iron availability and the hypoxic conditioning of the tumor with regard to tumor growth and we describe the relevance of therapeutic strategies to target such metabolic characteristics.

scholarly journals Evolution of sarcoma 180 in mice infected with Trypanosoma cruzi

1983 ◽  
Vol 78 (3) ◽  
pp. 237-244
Author(s):  
Fausto Edmundo Lima Pereira ◽  
William Assad Sassine ◽  
Dimith Chequer Bouhabib ◽  
Elton de Almeida Lucas
Keyword(s):  
Weight Gain ◽  
Trypanosoma Cruzi ◽  
Tumor Cells ◽  
Ascitic Fluid ◽  
Tumor Development ◽  
Sarcoma 180 ◽  
Tumor Inoculation ◽  
Time Intervals ◽  
Tumor Challenge ◽  
Ascites Formation

Mice infected with Trypanosoma cruzi were challenged with 2x10[raised to the power of 6] cells of sarcoma 180 (ascite tumor) by i.p. route, on day seven post infection. Tumor development was followed by evaluation of weight gain, by measurement of ascitic fluid produced and enumeration of tumor cells in ascitic fluid. Infected mice were more resitant to tumor development as demonstrated by reduction in ascites formation and by reduction in the number of tumor cells in ascitic fluid, at different time intervals after tumor challenge. The number of peritoneal cells exsudated after tumor inoculation was greater in infected mice than in controls. This increased resitance of mice infected with T. cruzi to tumor development could be due to the action of macrophages activated by the infection and by the action of endotoxins absorbed from the gut or produced by the own parasite.

scholarly journals Hmgb1-IL-23-IL-17-IL-6-Stat3 Axis Promotes Tumor Growth in Murine Models of Melanoma

2013 ◽  
Vol 2013 ◽  
pp. 1-13 ◽  
Author(s):  
Qiu Tang ◽  
Jian Li ◽  
Hongfei Zhu ◽  
Pan Li ◽  
Zhenwei Zou ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Tumor Cells ◽  
Tumor Size ◽  
Immune Surveillance ◽  
Tumor Development ◽  
Murine Models ◽  
Wild Type ◽  
Proliferating Cells ◽  
Melanoma Tumor ◽  
Tumor Bearing

In order to understand how tumor cells can escape immune surveillance mechanisms and thus develop antitumor therapies, it is critically important to investigate the mechanisms by which the immune system interacts with the tumor microenvironment. In our current study, IL-17 deficiency results in reduced melanoma tumor size, diminished numbers of proliferating cells and blood vessels, and decreased percentage of CD11b+Gr-1+MDSCs in tumor tissues. IL-17 promotes IL-6 induction and Stat3 activation. Treatment of Stat3 inhibitor WP1066 in B16-F10 tumor cells inoculated wild-type mice inhibits tumor growth. Additional administration of recombinant IL-6 into B16-F10 tumor-bearing IL-17−/−mice results in markedly increased tumor size and p-Stat3 expression, whereas additional recombinant IL-17 administration into B16-F10 tumor-bearing wild-type mice treated with anti-IL-6 mAb does not significantly alter the tumor growth and p-Stat3 expression. In our further study, blockade of Hmgb1-RAGE pathway inhibits melanoma tumor growth and reduces production of IL-23 and IL-17. All these data suggest that Hmgb1-IL-23-IL-17-IL-6-Stat3 axis plays a pivotal role in tumor development in murine models of melanoma, and blocking any portion of this axis will attenuate melanoma tumor growth.

The Syk Inhibitor TAK-659 Prevents Splenomegaly and Tumor Development in a Murine Model of EBV-Associated Lymphoma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4179-4179
Author(s):  
Osman Cen ◽  
Karuppiah Kannan ◽  
Jessica J. Huck ◽  
Jie Yu ◽  
Mengkun Zhang ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Tumor Cells ◽  
Cell Lines ◽  
Therapeutic Option ◽  
Tumor Development ◽  
Host Cells ◽  
Lymphoma Cells ◽  
Barr Virus ◽  
Transfer Models

Abstract Epstein-Barr virus (EBV) is associated with the development of several cancers including Burkitt's Lymphoma, Hodgkin Lymphoma, Nasopharyngeal and Gastric Carcinomas. EBV-encoded Latent Membrane Protein 2A (LMP2A), a BCR mimic, is expressed in cancer cells and is essential for transformation, migration and inhibition of differentiation. LMP2A/λ-MYC double transgenic mice develop splenomegaly and lymphoma much faster than mice that express Myc only. LMP2A induces cancer phenotype by recruiting and activating BCR signaling components such as Lyn and Syk kinases to the SH2 motifs found on its N terminal cytoplasmic domain. In this study, we explored inhibition of Syk kinase activity with a novel Syk/FLT-3 inhibitor TAK-659, in lymphomas from these transgenic mice to assess SYK inhibition as a potential therapeutic strategy for EBV-associated malignancies. The cell lines developed from LMP2A/Myc transgenic mice derived lymphomas showed higher basal pSYK levels than Myc lymphoma cell lines. TAK-659 treatment resulted in early apoptosis within 8hrs in LMP2A/Myc lymphoma cells in comparison to 24 hrs in Myc lymphoma cells. In both pre-tumor and tumor transfer models in vivo, compared with placebo and Myc tumors, LMP2A/MYC mice treated with TAK-659 did not develop splenomegaly and tumor development was totally inhibited in these mice indicating SYK signaling is essential for tumor development in LMP2A/Myc mice. In addition, metastasis of tumor cells into BM was abrogated. TAK-659 killed tumor cells but not host cells in spleen and tumors. Taken together our data show that TAK-659, even in low nanomolar concentrations, inhibits pSYK and induces apoptosis in LMP2A/Myc tumor cells. It also inhibits splenomegaly and tumor development in our autochthonous and syngeneic tumor transfer models of EBV-associated lymphoma by targeting tumor cells while sparing non-tumor cells. Therefore, TAK-659 may provide an effective therapeutic option for the treatment of EBV-associated malignancies and should be explored further in clinical trials. Disclosures Kannan: Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Huck:Takeda Pharmaceuticals International Co, Cambridge, MA: Employment. Yu:Takeda Pharmaceuticals International Co, Cambridge, MA: Employment. Zhang:Takeda Pharmaceuticals International Co, Cambridge, MA: Employment. Gordon:Northwestern University: Patents & Royalties: Patent for gold nanoparticles pending.

scholarly journals Functional malignant cell heterogeneity in pancreatic neuroendocrine tumors revealed by targeting of PDGF-DD

2016 ◽  
Vol 113 (7) ◽  
pp. E864-E873 ◽  
Author(s):  
Eliane Cortez ◽  
Hanna Gladh ◽  
Sebastian Braun ◽  
Matteo Bocci ◽  
Eugenia Cordero ◽  
...  
Keyword(s):  
Growth Factor ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Neuroendocrine Tumors ◽  
Tumor Development ◽  
Growth Factor Receptor ◽  
Malignant Cell ◽  
Platelet Derived Growth Factor ◽  
Cell Heterogeneity ◽  
Pancreatic Neuroendocrine Tumors

Intratumoral heterogeneity is an inherent feature of most human cancers and has profound implications for cancer therapy. As a result, there is an emergent need to explore previously unmapped mechanisms regulating distinct subpopulations of tumor cells and to understand their contribution to tumor progression and treatment response. Aberrant platelet-derived growth factor receptor beta (PDGFRβ) signaling in cancer has motivated the development of several antagonists currently in clinical use, including imatinib, sunitinib, and sorafenib. The discovery of a novel ligand for PDGFRβ, platelet-derived growth factor (PDGF)-DD, opened the possibility of a previously unidentified signaling pathway involved in tumor development. However, the precise function of PDGF-DD in tumor growth and invasion remains elusive. Here, making use of a newly generated Pdgfd knockout mouse, we reveal a functionally important malignant cell heterogeneity modulated by PDGF-DD signaling in pancreatic neuroendocrine tumors (PanNET). Our analyses demonstrate that tumor growth was delayed in the absence of signaling by PDGF-DD. Surprisingly, ablation of PDGF-DD did not affect the vasculature or stroma of PanNET; instead, we found that PDGF-DD stimulated bulk tumor cell proliferation by induction of paracrine mitogenic signaling between heterogeneous malignant cell clones, some of which expressed PDGFRβ. The presence of a subclonal population of tumor cells characterized by PDGFRβ expression was further validated in a cohort of human PanNET. In conclusion, we demonstrate a previously unrecognized heterogeneity in PanNET characterized by signaling through the PDGF-DD/PDGFRβ axis.

Platelet Glycoprotein Ibα Supports Primary Tumor Growth and Experimental Metastasis.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1463-1463
Author(s):  
Jerry Ware ◽  
Masahiko Zuka ◽  
Shaskank Jain ◽  
Susan Russell ◽  
Judith Dent ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Tumor Cells ◽  
Primary Tumor ◽  
Tumor Development ◽  
Target Organ ◽  
Primary Tumor Growth ◽  
Tumor Associated Macrophages ◽  
Syngeneic Tumor ◽  
Organ Colonization ◽  
Bernard Soulier Syndrome

Abstract Successful tumor formation and metastatic spread depend on the ability of tumor cells to interact with their host microenvironment. Studies from our groups and others indicate that platelets contribute to tumor host interactions through adhesive and stimulatory functions that may promote tumor growth and dissemination. Here we show that platelet receptor GPIbα plays a critical role in the ability of platelets to support primary tumor development and hematogenous metastasis. We previously developed knockout mice lacking platelet GP Ibα (GPIbαNull, a model of the human Bernard-Soulier syndrome) and mice missing GPIbα, but expressing a fusion protein of cytoplasmic GP Ibα and the extracytoplasmic domain of the interleukin-4 receptor (Ibα/IL-4R). Expression of the Ibα/IL-4R ameliorates macrothrombocytopenia, a characteristic of the Bernard-Soulier syndrome. However, both models result in a severe hemorrhagic state owing to the absence of GPIbα. Congenic mouse strains of both GP Ibα models were generated by 10-generation backcrosses with wild-type (WT) C57BL/6J mice to study the tumorgenic and metastatic activity of syngeneic tumor cells. To analyze primary tumor growth, Lewis lung carcinoma cells (D121) were injected intradermally in the dorsal flank of the hind limb (105 cells/injection) and tumor development analyzed in its initial and advanced stages. Seventeen days after injection, tumors in GPIbαNull and Ibα/IL-4R mice were several-fold smaller than those in WT C57BL/6J mice. Histological examination of early and end-stage tumors revealed three major differences: a severe and immediate onset of tumor necrosis, a lack of new blood vessels large enough to connect to the circulation, and a significant reduction in tumor-associated macrophages. While the proliferation rate of tumor cells in non-necrotic areas of the tumors was unaffected by the lack of GPIbα, the percentage of necrosis in these tumors was 6-fold increased in GPIbαNull mice. Each necrotic area showed increased hemorrhage in the absence of GPIbα. The overall density of microvessels in early primary tumors appeared unchanged, but the number of larger vessels associated with tumors was reduced ~2-fold and the density of tumor-associated macrophages was reduced ~6-fold compared to tumors developing in WT mice. To analyze a contribution of platelet GPIbα to hematogenous tumor metastasis, another syngeneic tumor cell model was used and B16F10.1 melanoma cells were injected into the tail vein (105 cells/mouse) of GPIbαNull, Ibα/IL-4R, or WT mice, to determine the ability of tumor cells to colonize the lungs 14 days later. In the absence of functional GPIbα, the number of metastatic foci at the surface of the lungs was significantly reduced (15-fold, p = 0.0002). These results indicate that successful target organ colonization by tumor cells from the blood stream is severely affected by the lack of extracytoplasmic GPIbα in Ibα/IL-4R animals, and not necessarily by the reduced number of platelets in GPIbαNull animals. The results demonstrate a significant involvement of platelet GP Ibα in primary tumor growth by affecting tumor angiogenesis and the recruitment of tumor-associated macrophages while providing evidence GPIbα directly contributes to target organ colonization by circulating tumor cells. These studies identify platelet GP Ibα as a potential new target for anti cancer therapy.

scholarly journals 153 Nanoscale, antigen-dependent, IL-12 delivery by CAR T cells plus PD-L1 blockade for cancer treatment

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A162-A163
Author(s):  
Zhifen Yang ◽  
Francesco Marincola
Keyword(s):  
T Cells ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Car T Cells ◽  
Car T ◽  
Ifn Γ ◽  
High Doses ◽  
Fadu Cells

BackgroundInterleukin(IL)-12 activates T cells pivoting the switch that turns lingering inflammation into acute inflammation and cancer rejection. However, its clinical utilization is limited by severe systemic toxicity. IL-12 is a potent inducer of PD-1 expression in T cells. Here, we present a conditional, antigen-dependent, non-editing CRISPR-activation (CRISPRa) circuit (RB-312) that delivers nanoscale doses of IL-12 for autocrine activation of CAR-T cells. RB-312 was also tested in combination with PD-L1 blocking antibody (atezolizumab).MethodsRB-312 is a CAR T cell engineered to express the IL-12 heterodimer via conditional transcription of its two endogenous subunits p35 and p40. The circuit includes two lentiviral constructs with one encoding HER2-specific chimeric antigen receptor and two sgRNAs targeting IL-12A or IL-12B and the other encoding linker for activation of T cells, complexed to dead Cas9 (dCas9)-VP64-p65-Rta transcriptional activator (VPR) (LdCV). Activation of CAR allows the release of dCas9 for nuclear localization and hence conditionally and reversibly induces the secretion of IL-12 p70 heterodimer.ResultsRB-312 induced low concentrations of IL-12 upon exposure to HER2+ FaDu cancer cells engineered to overexpress PD-L1 and this resulted in significantly enhanced production of IFN-γ, cytotoxicity and CAR-T proliferation (figure 1A). These effects were comparable to co-culturing conventional HER2 CAR with FaDu cells modified to express high doses of IL-12 (figure 1B). In vivo administration of RB-312 significantly enhanced survival of mice carrying FaDu xenografts compared to mice treated with the respective conventional HER2 CAR or cRB-312 (control lacking the IL-12 sgRNAs, figure 2A). RB-312 induced a strong upregulation of PD-1 in CAR-T cells in vivo (figure 2B). The critical role of the PD-1/PD-L1 interaction was demonstrated in vitro by comparing RB-312 proliferation when exposed to FaDu overexpressing PD-L1 or PD-L1 knock out cells (figure 3A). Indeed, combined treatment of RB-312 and atezolizumab resulted in significant reduction in tumor growth (figure 3B and C) and significantly enhanced survival (figure 3D).Abstract 153 Figure 1Conditional autocrine release of nanoscale-dose p70/IL-12 by RB-312 resulting in enhanced IFN-γ production in vitro after three days of exposure to HER2+ FaDu cells (figure 1A), and the level of IFN-γ production was comparable to co-culturing conventional HER2-specific CAR-T cells with a modified FaDu cell line engineered to constitutively express high doses of IL-12 (FaDu/IL-12, figure 1B)Abstract 153 Figure 2Intra-tumoral administration of RB-312 extended survival in mice carrying FaDu xenografts compared to NT (non-transduced T cells), HER2 CAR (conventional HER2 CAR-T cells) and cRB-312 CAR-T cells missing the sgRNAs for the two IL-12 subunits (figure 2A). Analysis of necropsy material demonstrated that PD-1 expression was dramatically increased in RB-312 compared with the respective control cRB-312 (figure 2B)Abstract 153 Figure 3RB-312 cellular function in vivo. PD-L1 expression by FaDu cell lines is a critical mechanism of repression of RB-312 function. In vitro CAR-T proliferation of RB-312 upon stimulation with FaDu tumor cells (orange solid lines) or FaDu/PD-L1 knockout tumor cells (orange dashed lines) over 6-day time course (figure 3A). In vivo efficacy of intra-tumoral RB-312 against FaDu tumor cells with (orange solid lines) or without (orange dashed lines) addition of PD-L1 blocking antibody atezolizumab (administered intravenously at 5 mg/kg twice per week), as shown by tumor growth followed till day 29 and scatter plot at day 29 (figure 3B), tumor growth spider plots (figure 3C) and Kaplan-Meier survival curve (figure 3D)ConclusionsWe concluded that addition of a Th1 polarizing component such as IL-12 exponentially increases the efficacy of reprogrammed CAR-T cells by combining enhancement of effector functions to cellular fitness. The autocrine effects of nanoscale IL-12 production limit the risk of off-tumor leakage and systemic toxicity. Here, we tested the combination of PD-1/PD-L1 blockade with IL-12-induced CAR-T cell activation demonstrated dramatic synergistic effects. We are currently evaluating the intrinsic combination of IL-12 delivery and PD-L1 resistance for the next generation of RB-312 product eliminating the need for systemic checkpoint blockade.

scholarly journals “Abscopal” Effect of Radiation Therapy Combined with Immune-Therapy Using IFN-γ Gene Transfected Syngeneic Tumor Cells, in Rats with Bilateral Implanted N29 Tumors

2011 ◽  
Vol 2011 ◽  
pp. 1-13 ◽  
Author(s):  
Bertil R. R. Persson ◽  
Catrin Bauréus Koch ◽  
Gustav Grafström ◽  
Crister Ceberg ◽  
Per Munck af Rosenschöld ◽  
...  
Keyword(s):  
Growth Rate ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Immune Therapy ◽  
Tumor Growth Rate ◽  
Target Area ◽  
Rat Glioma ◽  
Fischer 344 ◽  
Ifn Γ ◽  
The Right

The tumor growth rate response was studied on N29 rat glioma tumor cells subcutaneously implanted on both hind legs of Fischer-344 rats. At around 30 days after inoculation, RT was given with 60Co gamma radiation with 4 daily fractions of 5 Gy only to the right-lateral tumors. At days 26, 42, and 54 after inoculation, immunization was performed with irradiated syngeneic IFNγ-gene transfected cells. Tumor growth rate (TGR % per day) of the right-lateral irradiated tumor was significantly decreased (P<0.01) after RT alone and with the combination of RT and immunization. But immunization alone gave no significant decrease of the TGR but significantly increased time of survival. The TGR of the unirradiated left-lateral tumors was significantly decreased (P<0.02) only in the group of rats treated with RT alone. It is apparent that tumor cells killed by the radiation mediate suppression of tumor cells outside the target area. This effect is called the abscopal effect.

scholarly journals Paradoxical Roles of Peritumoral Hepatic Stellate Cells in Liver Tumorigenesis in Mice: Retarding Tumor Growth and Promoting Tumor Dissemination

2021 ◽  
Author(s):  
Cheng Tian ◽  
Liyuan Li ◽  
Li Fan ◽  
Anthony Brown ◽  
Eric J. Norris ◽  
...  
Keyword(s):  
Liver Cancer ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Liver Tumor ◽  
Hepatic Stellate Cells ◽  
Mouse Liver ◽  
Tumor Development ◽  
Stellate Cells ◽  
Growth Suppression ◽  
Tumor Dissemination

ABSTRACTBackground and RationaleCancer is increasingly being viewed as an ecosystem in which tumor cells coevolve and cooperate with host cells. In liver cancer, extensive biological changes have been reported in parenchymal hepatocytes (HCs) and non-parenchymal cells (NPCs) in the peritumoral microenvironment (pTME). However, it remains controversial how individ ual pTME populations contribute to liver tumorigenesis. We aim to develop an efficient in vitro model system to dissect the intricate relationship between liver tumor and its surroundings.ResultsIn this study, we established three-dimensional spheroid cocultures of primary mouse liver cells. We show that spheroids of HCs and NPCs can be readily generated in micropatterned multiwell plates. When cocultured with liver tumor spheroids, NPC spheroids, but not HC spheroids, exhibited a potent suppression activity on tumor cell growth. However, tumor cells (T) in NPC-T culture, while enduring growth suppression, showed a significant increase in dissemination compared to that in HC-T or T-alone culture. We then showed that hepatic stellate cells (HSCs) in NPCs are a key contributor to this NPC-mediated tumor growth suppression and dissemination augmentation. We validated our results in a highly metastatic orthotopic liver cancer allograft model. We showed that tumor development in this model induced widespread activation of HSCs in the pTME, and the accumulation of peritumoral HSCs at the tumor border is associated with retarded tumor growth and enhanced tumor dissemination.ConclusionThis study reveals a paradoxical role of peritumoral HSCs in liver tumorigenesis beyond being simply pro- or anti-tumorigenic. Tumor development in mouse liver induces activation of peritumoral HSCs that effectively retard tumor growth but simultaneously promote tumor dissemination.

Melatonin modifies tumor hypoxia and metabolism by inhibiting HIF-1α and energy metabolic pathway in the in vitro and in vivo models of breast cancer

2019 ◽  
Vol 2 (4) ◽  
pp. 83-98 ◽  
Author(s):  
André De Lima Mota ◽  
Bruna Vitorasso Jardim-Perassi ◽  
Tialfi Bergamin De Castro ◽  
Jucimara Colombo ◽  
Nathália Martins Sonehara ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Glucose Metabolism ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Carbonic Anhydrases ◽  
In Vivo Models ◽  
Ca Ix ◽  
Gene And Protein Expression

Breast cancer is the most common cancer among women and has a high mortality rate. Adverse conditions in the tumor microenvironment, such as hypoxia and acidosis, may exert selective pressure on the tumor, selecting subpopulations of tumor cells with advantages for survival in this environment. In this context, therapeutic agents that can modify these conditions, and consequently the intratumoral heterogeneity need to be explored. Melatonin, in addition to its physiological effects, exhibits important anti-tumor actions which may associate with modification of hypoxia and Warburg effect. In this study, we have evaluated the action of melatonin on tumor growth and tumor metabolism by different markers of hypoxia and glucose metabolism (HIF-1α, glucose transporters GLUT1 and GLUT3 and carbonic anhydrases CA-IX and CA-XII) in triple negative breast cancer model. In an in vitro study, gene and protein expressions of these markers were evaluated by quantitative real-time PCR and immunocytochemistry, respectively. The effects of melatonin were also tested in a MDA-MB-231 xenograft animal model. Results showed that melatonin treatment reduced the viability of MDA-MB-231 cells and tumor growth in Balb/c nude mice (p <0.05). The treatment significantly decreased HIF-1α gene and protein expression concomitantly with the expression of GLUT1, GLUT3, CA-IX and CA-XII (p <0.05). These results strongly suggest that melatonin down-regulates HIF-1α expression and regulates glucose metabolism in breast tumor cells, therefore, controlling hypoxia and tumor progression. 

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