scholarly journals Lactate and Acidity in the Cancer Microenvironment

2020 ◽  
Vol 4 (1) ◽  
pp. 141-158 ◽  
Author(s):  
Scott K. Parks ◽  
Wolfgang Mueller-Klieser ◽  
Jacques Pouysségur
Keyword(s):  
Lactic Acid ◽  
Immune Responses ◽  
Tumor Growth ◽  
Tumor Response ◽  
Intracellular Acidosis ◽  
Tumor Environment ◽  
Aggressive Tumors ◽  
Lactate Dehydrogenases ◽  
Global Reduction ◽  
Xenograft Tumor Growth

Fermentative glycolysis, an ancient evolved metabolic pathway, is exploited by rapidly growing tissues and tumors but also occurs in response to the nutritional and energetic demands of differentiated tissues. The lactic acid it produces is transported across cell membranes through reversible H+/lactate− symporters (MCT1 and MCT4) and is recycled in organs as a major metabolic precursor of gluconeogenesis and an energy source. Concentrations of lactate in the tumor environment, investigated utilizing an induced metabolic bioluminescence imaging (imBI) technique, appear to be dominant biomarkers of tumor response to irradiation and resistance to treatment. Suppression of lactic acid formation by genetic disruption of lactate dehydrogenases A and B in aggressive tumors reactivated OXPHOS (oxidative phosphorylation) to maintain xenograft tumor growth at a halved rate. In contrast, disruption of the lactic acid transporters MCT1/4 suppressed glycolysis, mTORC1, and tumor growth as a result of intracellular acidosis. Furthermore, the global reduction of tumor acidity contributes to activation of the antitumor immune responses, offering hope for future clinical applications.

823 CD4 T cells are essential for an anti-tumor effect in a B78 murine melanoma tumor model

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A873-A873
Author(s):  
Arika Feils ◽  
Mackenzie Heck ◽  
Anna Hoefges ◽  
Peter Carlson ◽  
Luke Zangl ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Growth ◽  
Cd4 T Cells ◽  
Tumor Response ◽  
Immune Cell ◽  
Cd8 T Cell ◽  
Mhc I ◽  
Mhc Ii ◽  
Flow Cytometric

BackgroundMice bearing B78 melanoma tumors can be cured using an in situ vaccine (ISV) regimen that includes radiation (RT) together with immunocytokine (tumor-targeting mAb conjugated to IL-2). B78 melanoma cells, derived from B16 cells, express minimal to no MHC-I but express MHC-II upon IFN-g/TNF-a stimulation. Although B78 cells are primarily MHC-I-deficient, an increased CD8 T cell infiltration into the tumor microenvironment (TME) has been shown following ISV.1 To further investigate the potential role of specific immune cell lineages in the B78 anti-tumor response to ISV, immune subset depletion studies and flow cytometric analyses were performed.MethodsC57BL/6 mice bearing B78 tumors were depleted of immune cell subsets with mAbs (anti-CD4, anti-CD8, anti-NK1.1, or Rat IgG control) for 3 weeks during the course of treatment. Treatment groups included no treatment, RT (12 Gy), or ISV (RT D0 and immunocytokine D5-D9). 6 mice/group (repeated three times) were followed for survival/tumor growth, and flow cytometry studies included 4 mice/group, sacrificed on D8 and D13 following the start of ISV.ResultsMice depleted of CD4 T cells during the course of ISV showed a significant reduction of anti-tumor effect as compared to mice treated with ISV/Rat IgG (pConclusionsThese studies suggest that CD4 T cells are essential for an anti-tumor response in the B78 melanoma model. In vivo depletion data show that CD4 T cells, but not CD8 or NK cells, are required for a decrease in tumor growth via ISV. Flow cytometric analyses suggest an interplay between CD4 and CD8 T cells as indicated by a decrease in CD8/IFN-g expression following ISV in the absence of CD4 T cells. The role that MHC-I and MHC-II expression plays in this CD4/CD8 T cell anti-tumor response is under investigation. In future studies, B78 melanoma may serve as a critical syngeneic model for development of more effective immunotherapy treatment regimens.Ethics ApprovalAll animal experiments were performed in accordance with protocols approved by Animal Care and Use Committees of the University of Wisconsin-Madison.ReferenceMorris Z, Guy E, Francis D, et al. In situ tumor vaccination by combining local radiation and tumor-specific antibody or immunocytokine treatments. Cancer Res 2016;76(13):3929-3941.

Circ_002059 suppresses cell proliferation and migration of gastric cancer via miR-182/MTSS1 axis

2021 ◽  
Vol 53 (4) ◽  
pp. 454-462
Author(s):  
Ting Li ◽  
Xiaomin Zuo ◽  
Xiangling Meng
Keyword(s):  
Gastric Cancer ◽  
Cell Proliferation ◽  
Tumor Growth ◽  
Luciferase Reporter ◽  
Metastasis Suppressor ◽  
Xenograft Tumor ◽  
Cell Proliferation And Migration ◽  
And Migration ◽  
Xenograft Tumor Growth ◽  
Proliferation And Migration

Abstract Circular RNAs (circRNAs) play either oncogenic or tumor suppressive roles in gastric cancer (GC). A previous study demonstrated that circ_002059, a typical circRNA, was downregulated in GC tissues. However, the role and mechanism of circ_002059 in GC development are still unknown. In this study, the levels of circ_002059, miR-182, and metastasis suppressor-1 (MTSS1) were examined by real-time quantitative polymerase chain reaction and western blot analysis. Cell proliferation and migration were evaluated by MTT assay and Transwell migration assay, respectively. The interactions between miR-182 and circ_002059 or MTSS1 were analyzed by dual-luciferase reporter assay. A GC xenograft model was established to validate the role of circ_002059 in GC progression in vivo. Overexpression of circ_002059 significantly inhibited, whereas knockdown of circ_002059 notably facilitated, cell proliferation and migration in GC cells. MTSS1 was found to be a direct target of miR-182 and circ_002059 upregulated MTSS1 expression by competitively sponging miR-182. Transfection with miR-182 mimic and MTSS1 silencing abated the inhibitory effect of circ_002059 on GC progression. Circ_002059 inhibited GC cell xenograft tumor growth by regulating miR-182 and MTSS1 expression. Collectively, Circ_002059 inhibited GC cell proliferation and migration in vitro and xenograft tumor growth in mice, by regulating the miR-182/MTSS1 axis.

scholarly journals Temporal Changes in Immune Responses within the Tumor Microenvironment in the 4T1.2-HER2 Mammary Tumor Model

2021 ◽  
Author(s):  
Yitong Xu ◽  
Connie Rogers
Keyword(s):  
Immune Responses ◽  
Tumor Growth ◽  
Immune Cells ◽  
Tumor Regression ◽  
Tumor Model ◽  
Second Phase ◽  
Tumor Inoculation ◽  
Cancer Model ◽  
Breast Cancer Model ◽  
Initial Tumor

Abstract Background: The murine 4T1.2 triple-negative breast cancer model is widely used, but is poorly immunogenic with no defined tumor-associated antigens. A modified 4T1.2 model has been developed that stably expresses a surrogate tumor antigen, human epidermal growth factor receptor-2 (HER2). The goal of the current study was to characterize host immune responses in the 4T1.2-HER2 tumor model, focusing on the tumor microenvironment (TME) during the early stage of tumor development. Methods: Female BALB/c mice were orthotopically inoculated with 4T1.2-HER2 tumor cells and sacrificed at day (D) 6, 9, 12, 15 and 18 post tumor inoculation. The phenotype and function of tumor-infiltrating immune cells were assessed. Results: 4T1.2 and 4T1.2-HER2 tumor cells had similar proliferation rates in vitro. In contrast to the rapid progression of the parental 4T1.2 model, the 4T1.2-HER2 model demonstrated initial tumor growth followed by spontaneous tumor regression by D18 post tumor inoculation, which was not observed in scid mice. Following tumor regression, mice demonstrated either a second phase of tumor outgrowth or complete tumor rejection. Within the TME, the percentage of T cells was reduced at D9 and increased during tumor regression through D18 (p<0.05), whereas the percentage of myeloid-derived suppressor cells (MDSCs) increased during the initial tumor growth and was reduced by D18 (p<0.01). There was a stepwise increase in the percentage of IFNg+, IL-2+ and perforin+ T cells and NK cells peaking at D12-15. Furthermore, tumor regression occurred concurrently with HER2-specific IFNg production from tumor-infiltrating immune cells at D12 and D15 (p<0.05). During the second phase of 4T1.2-HER2 tumor growth, tumor volume was negatively correlated with immune infiltration (r=0.662, p=0.052). Conclusions: These results suggest that the integration of a surrogate tumor antigen, human HER2, into the clinically relevant, yet poorly immunogenic 4T1.2 breast cancer model enhanced its immunogenicity and induced HER2-specific immune responses.

scholarly journals GRP94 (gp96) and GRP94 N-Terminal Geldanamycin Binding Domain Elicit Tissue Nonrestricted Tumor Suppression

2002 ◽  
Vol 196 (11) ◽  
pp. 1447-1459 ◽  
Author(s):  
Julie C. Baker-LePain ◽  
Marcella Sarzotti ◽  
Timothy A. Fields ◽  
Chuan-Yuan Li ◽  
Christopher V. Nicchitta
Keyword(s):  
Immune Responses ◽  
Tumor Growth ◽  
Tumor Suppression ◽  
Protective Immunity ◽  
Chemical Carcinogenesis ◽  
Binding Domain ◽  
Primary Role ◽  
Metastatic Progression ◽  
Peptide Antigens ◽  
Tissue Of Origin

In chemical carcinogenesis models, GRP94 (gp96) elicits tumor-specific protective immunity. The tumor specificity of this response is thought to reflect immune responses to GRP94-bound peptide antigens, the cohort of which uniquely identifies the GRP94 tissue of origin. In this study, we examined the apparent tissue restriction of GRP94-elicited protective immunity in a 4T1 mammary carcinoma model. We report that the vaccination of BALB/c mice with irradiated fibroblasts expressing a secretory form of GRP94 markedly suppressed 4T1 tumor growth and metastasis. In addition, vaccination with irradiated cells secreting the GRP94 NH2-terminal geldanamycin-binding domain (NTD), a region lacking canonical peptide-binding motifs, yielded a similar suppression of tumor growth and metastatic progression. Conditioned media from cultures of GRP94 or GRP94 NTD-secreting fibroblasts elicited the up-regulation of major histocompatibility complex class II and CD86 in dendritic cell cultures, consistent with a natural adjuvant function for GRP94 and the GRP94 NTD. Based on these findings, we propose that GRP94-elicited tumor suppression can occur independent of the GRP94 tissue of origin and suggest a primary role for GRP4 natural adjuvant function in antitumor immune responses.

scholarly journals Multiple Biological Activities of Lactic Acid in Cancer: Influences on Tumor Growth,Angiogenesis and Metastasis

2012 ◽  
Vol 18 (10) ◽  
pp. 1319-1330 ◽  
Author(s):  
Suveera Dhup ◽  
Rajesh Kumar Dadhich ◽  
Paolo Ettore Porporato ◽  
Pierre Sonveaux
Keyword(s):  
Lactic Acid ◽  
Tumor Growth ◽  
Biological Activities

scholarly journals  -Mangostin, a xanthone from mangosteen fruit, promotes cell cycle arrest in prostate cancer and decreases xenograft tumor growth

2011 ◽  
Vol 33 (2) ◽  
pp. 413-419 ◽  
Author(s):  
J. J. Johnson ◽  
S. M. Petiwala ◽  
D. N. Syed ◽  
J. T. Rasmussen ◽  
V. M. Adhami ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Tumor Growth ◽  
Cell Cycle Arrest ◽  
Xenograft Tumor ◽  
Cycle Arrest ◽  
Xenograft Tumor Growth
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