scholarly journals Paracrine Activin-A signaling promotes melanoma growth and metastasis through immune evasion

2017 ◽  
Author(s):  
Prudence Donovan ◽  
Olivier A. Dubey ◽  
Susanna Kallioinen ◽  
Katherine W. Rogers ◽  
Katja Muehlethaler ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tumor Cell ◽  
Melanoma Cell ◽  
Immune Evasion ◽  
Muscle Wasting ◽  
Receptor Activation ◽  
Activin A ◽  
Tumor Cell Proliferation ◽  
Tumor Vascularization ◽  
Promoting Effect

ABSTRACTThe secreted growth factor Activin-A of the TGFβ family and its receptors can promote or inhibit several cancer hallmarks including tumor cell proliferation and differentiation, vascularization, lymphangiogenesis and inflammation. However, a role in immune evasion and its relationship with tumor-induced muscle wasting and tumor vascularization, and the relative contributions of autocrine versus paracrine Activin signaling remain to be evaluated. To address this, we compared the effects of truncated soluble Activin receptor II B as a ligand trap, or constitutively active mutant type IB receptor versus secreted Activin-A or the related ligand Nodal in mouse and human melanoma cell lines and tumor grafts. We found that while cell-autonomous receptor activation arrested tumor cell proliferation, Activin-A secretion stimulated melanoma cell dedifferentiation and tumor vascularization by functional blood vessels, and it increased primary and metastatic tumor burden and muscle wasting. Importantly, in mice with impaired adaptive immunity, the tumor-promoting effect of Activin-A was lost despite sustained vascularization and cachexia, suggesting that Activin-A promotes melanoma progression by inhibiting anti-tumor immunity. Paracrine Activin-A signaling emerges as a potential target for personalized therapies, both to reduce cachexia and to enhance the efficacy of immunotherapies.

scholarly journals Interruption of Activin A Autocrine Regulation by Antisense Oligodeoxynucleotides Accelerates Liver Tumor Cell Proliferation*

Endocrinology ◽  
1999 ◽  
Vol 140 (7) ◽  
pp. 3125-3132 ◽  
Author(s):  
Kazuaki Takabe ◽  
Jean-Jacques Lebrun ◽  
Yoji Nagashima ◽  
Yasushi Ichikawa ◽  
Masato Mitsuhashi ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tumor Cell ◽  
Liver Tumor ◽  
Activin A ◽  
Antisense Oligodeoxynucleotides ◽  
Tumor Cell Proliferation ◽  
Autocrine Regulation ◽  
Liver Tumor Cell

scholarly journals Bone Marrow Suppression by c-Kit Blockade Enhances Tumor Growth of Colorectal Metastases through the Action of Stromal Cell-Derived Factor-1

2012 ◽  
Vol 2012 ◽  
pp. 1-12
Author(s):  
Kathrin Rupertus ◽  
Gudrun C. Y. Haberl ◽  
Claudia Scheuer ◽  
Michael D. Menger ◽  
Martin K. Schilling ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Proliferation ◽  
Tumor Cell ◽  
Stromal Cell ◽  
Bone Marrow Suppression ◽  
Colorectal Metastases ◽  
Tumor Cell Proliferation ◽  
Tumor Vascularization ◽  
Cell Engraftment ◽  
Stromal Cell Derived Factor

Background. Mobilization of c-Kit+hematopoietic cells (HCs) contributes to tumor vascularization. Whereas survival and proliferation of HCs are regulated by binding of the stem cell factor to its receptor c-Kit, migration of HCs is directed by stromal cell-derived factor (SDF)-1. Therefore, targeting migration of HCs provides a promising new strategy of anti-tumor therapy.Methods. BALB/c mice () were pretreated with an anti-c-Kit antibody followed by implantation of CT26.WT-GFP colorectal cancer cells into dorsal skinfold chambers. Animals () additionally received a neutralizing anti-SDF-1 antibody. Animals () treated with a control antibody served as controls. Investigations were performed using intravital fluorescence microscopy, immunohistochemistry, flow cytometry and western blot analysis.Results. Blockade of c-Kit significantly enhanced tumor cell engraftment compared to controls due to stimulation of tumor cell proliferation and invasion without markedly affecting tumor vascularization. C-Kit blockade significantly increased VEGF and CXCR4 expression within the growing tumors. Neutralization of SDF-1 completely antagonized this anti-c-Kit-associated tumor growth by suppression of tumor neovascularization, inhibition of tumor cell proliferation and reduction of muscular infiltration.Conclusion. Our study indicates that bone marrow suppression via anti-c-Kit pretreatment enhances tumor cell engraftment of colorectal metastases due to interaction with the SDF-1/CXCR4 pathway which is involved in HC-mediated tumor angiogenesis.

Research into P2X purinergic receptor function in tumor growth has made substantial progress with potential gene therapy targeting

2021 ◽  
Author(s):  
Moataz Dowaidar
Keyword(s):  
Cell Proliferation ◽  
Tumor Cell ◽  
Tumor Progression ◽  
Purinergic Receptors ◽  
Purinergic Receptor ◽  
Receptor Activation ◽  
Tumor Formation ◽  
Tumor Cell Proliferation ◽  
Tumor Treatment ◽  
Substantial Progress

Tumor development is a complex molecular process, and treating it remains the most challenging problem to address at this moment. It is vital to comprehend and explain the molecular foundation of cancer genesis, as well as to uncover novel targets for tumor prevention and therapy. Thankfully, research into the role of P2X purinergic receptors in tumor formation has made substantial progress. The activation of P2X purinergic receptors by ATP aids the control of tumor cell proliferation and fate. P2X purinergic receptor activation can either stimulate or inhibit tumor cell proliferation. While the effects of P2X4 and P2X7 receptors are the most obvious, they can act directly on tumor cells as well as indirectly through immune cells to control tumor progression. In most studies, P2X purinergic receptor antagonists have been shown to prevent their activation, reduce their expression level, and halt tumor progression. As a result, developing P2X-specific antagonists or selective antagonists for tumor treatment has a lot of potential and might be a novel molecular pharmacological target for tumor treatment.

Expression of β-Catenin in Hepatocellular Carcinoma

2001 ◽  
Vol 71 (3) ◽  
pp. 116-125
Author(s):  
Norina Basa ◽  
Daniela Lazar ◽  
Remus Cornea ◽  
Sorina Taban ◽  
Melania Ardelean ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Tumor Cell ◽  
Mitotic Index ◽  
Histological Grade ◽  
Proliferation Index ◽  
Tumor Cell Proliferation ◽  
Ki 67 ◽  
B Virus ◽  
Development And Evolution

Alteration of β-catenin expression is involved in the development and evolution of hepatocellular carcinoma (HCC); β-catenin is able to influence tumor cell proliferation. We analyzed the immunohistochemical (IHC) expression of β-catenin on a group of 32 patients diagnosed with HCC using the anti-β-catenin monoclonal antibody (clone E247). We correlated the expression of β-catenin with the proliferation index of Ki-67 (PI Ki-67), the mitotic index (MI) and other clinical and pathological features. We observed an altered β-catenin expression in 58.38% of all HCC cases. This expression was insignificantly correlated with tumor size (]5 cm) (p = 0.683), histological grade G1-G2 (p = 0.307), vascular invasion (p = 0.299) and advanced pT stage (p = 0.453); we obtained a significantly higher MI in HCC with altered β-catenin expression (p = 0.018), as compared to HCC without overexpression (1.66 � 1.37) (p = 0.038) and a PI Ki-67 of 22.49 � 20.1 and 28.24 � 18.2, respectively in tumors with altered β-catenin expression with insignificant differences compared to HCC without overexpression (25.95 � 15.2) (p = 0.682 and p = 0.731, respectively). According to the results we obtained, aberrant β-catenin expression in HCC was correlated with a high mitotic index, therefore playing an important role in tumor progression by stimulating tumor cell proliferation; non-nuclear β-catenin overexpression can have a pathological significance in HCC, especially in cases of HCC associated with hepatitis B virus (HBV) infection.

scholarly journals Combined Application of Pan-AKT Inhibitor MK-2206 and BCL-2 Antagonist Venetoclax in B-Cell Precursor Acute Lymphoblastic Leukemia

2021 ◽  
Vol 22 (5) ◽  
pp. 2771
Author(s):  
Anna Richter ◽  
Elisabeth Fischer ◽  
Clemens Holz ◽  
Julia Schulze ◽  
Sandra Lange ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tumor Cell ◽  
Cell Lines ◽  
Morphological Changes ◽  
Synergistic Effects ◽  
Lymphoblastic Leukemia ◽  
Tumor Cell Proliferation ◽  
Akt Inhibitor ◽  
Akt Phosphorylation ◽  
Combined Application

Aberrant PI3K/AKT signaling is a hallmark of acute B-lymphoblastic leukemia (B-ALL) resulting in increased tumor cell proliferation and apoptosis deficiency. While previous AKT inhibitors struggled with selectivity, MK-2206 promises meticulous pan-AKT targeting with proven anti-tumor activity. We herein, characterize the effect of MK-2206 on B-ALL cell lines and primary samples and investigate potential synergistic effects with BCL-2 inhibitor venetoclax to overcome limitations in apoptosis induction. MK-2206 incubation reduced AKT phosphorylation and influenced downstream signaling activity. Interestingly, after MK-2206 mono application tumor cell proliferation and metabolic activity were diminished significantly independently of basal AKT phosphorylation. Morphological changes but no induction of apoptosis was detected in the observed cell lines. In contrast, primary samples cultivated in a protective microenvironment showed a decrease in vital cells. Combined MK-2206 and venetoclax incubation resulted in partially synergistic anti-proliferative effects independently of application sequence in SEM and RS4;11 cell lines. Venetoclax-mediated apoptosis was not intensified by addition of MK-2206. Functional assessment of BCL-2 inhibition via Bax translocation assay revealed slightly increased pro-apoptotic signaling after combined MK-2206 and venetoclax incubation. In summary, we demonstrate that the pan-AKT inhibitor MK-2206 potently blocks B-ALL cell proliferation and for the first time characterize the synergistic effect of combined MK-2206 and venetoclax treatment in B-ALL.

scholarly journals Validation of MicroRNA-188-5p Inhibition Power on Tumor Cell Proliferation in Papillary Thyroid Carcinoma

2020 ◽  
Vol 29 ◽  
pp. 096368972091830 ◽  
Author(s):  
Ping Zhou ◽  
Andrew Irving ◽  
Huifang Wu ◽  
Juan Luo ◽  
Johana Aguirre ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Papillary Thyroid Carcinoma ◽  
Thyroid Carcinoma ◽  
Tumor Cell ◽  
Cellular Proliferation ◽  
Tumor Cell Proliferation ◽  
Papillary Thyroid ◽  
Tumor Tissues ◽  
Potential Biomarker ◽  
And Function

Given the crucial role of microRNAs in the cellular proliferation of various types of cancers, we aimed to analyze the expression and function of a cellular proliferation-associated miR-188-5p in papillary thyroid carcinoma (PTC). Here we demonstrate that miR-188-5p is downregulated in PTC tumor tissues compared with the associated noncancerous tissues. We also validate that the miR-188-5p overexpression suppressed the PTC cancer cell proliferation. In addition, fibroblast growth factor 5 (FGF5) is observed to be downregulated in the PTC tumor tissues compared with the associated noncancerous tissues. Subsequently, FGF5 is identified as the direct functional target of miR-188-5p. Moreover, the silencing of FGF5 was found to inhibit PTC cell proliferation, which is the same pattern as miR-188-5p overexpression. These results suggest that miR-188-5p-associated silencing of FGF5 inhibits tumor cell proliferation in PTC. It also highlights the importance of further evaluating miR-188-5p as a potential biomarker and therapy target in PTC.

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