scholarly journals Role of ADP receptors on platelets in the growth of ovarian cancer

Blood ◽  
2017 ◽  
Vol 130 (10) ◽  
pp. 1235-1242 ◽  
Author(s):  
Min Soon Cho ◽  
Kyunghee Noh ◽  
Monika Haemmerle ◽  
Dan Li ◽  
Hyun Park ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Murine Models ◽  
P2y12 Inhibitor ◽  
Key Points ◽  
Adp Receptors

Key Points P2Y12 is important in the interaction between platelets and cancer cells. A P2Y12 inhibitor or P2Y12 deficiency reduces tumor growth in murine models of ovarian cancer.

scholarly journals Platelets Promote Activation of the Complement System in Ovarian Cancer

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4970-4970
Author(s):  
Omayra Gonzalez Pagan ◽  
Min Soon Cho ◽  
Vahid Afshar-Kharghan
Keyword(s):  
Ovarian Cancer ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Complement System ◽  
Complement Activation ◽  
Platelet Inhibition ◽  
Ovarian Cancer Cells ◽  
Murine Models ◽  
Mesenchymal Transition ◽  
The Complement System

Abstract Platelets promote metastasis and growth of ovarian cancer. We have shown that platelets extravasate into the tumor microenvironment (TME) and increase proliferation and epithelial-mesenchymal transition (EMT) in ovarian cancer cells. We have also shown that activation of the complement system in TME of ovarian cancer enhances tumor growth. Ovarian cancer cells secrete complement proteins that upon activation in the TME increase proliferation of cancer cells and promote EMT via an autocrine pathway. The activators of the complement system in the TME have not been identified. We have demonstrated that upon activation platelets activate the complement system on their surface. In the current study, we examined whether extravasated platelets inside tumors contribute to the complement activation in the TME. 1) We examined the effect of antiplatelet reagents on platelet extravasation into TME, using murine models of ovarian cancer. Tumors induced by injection of ovarian cancer cells into the peritoneum of Nu/Nu mice were resected after 6-8 weeks and the number of extravasated platelets was determined by immunostaining tumor sections and counting the number CD42 (GPIb) positive cells that were outside the blood vessels (CD31 positive). We found that platelet extravasation is an active process and platelet inhibition by aspirin or ticagrelor reduces the number of extravasated platelets. Furthermore, P2Y12 deficient platelets extravasate less than normal platelets. In all of these experiments, the number of extravasated red blood cells were significantly less than extravasated platelets and was not affected by the inhibition of platelets. 2) We examined the effect of platelet inhibition on the activation of the complement system in the TME. We immunostained resected tumors from aspirin- or ticagrelor-treated tumor-bearingmice and from P2Y12-deficient tumor-bearingmice for the endproductof complement activation (C5b-9 or membrane attack complex). Inhibition of platelet function by aspirin or ticagrelor,or the presence of hypoactive platelets in P2Y12 deficient mice reduced the amount of C5b-9 deposited in the tumors induced in murine models of ovarian cancer. Our result showed that complement activation in the TME is at least partially dependent onextravasated platelets. We propose that platelets in addition to directly increasing proliferation of ovarian cancer cells, also enhance tumor growth by activating the complement system in the vicinity of cancer cells. Our study links platelets, complement activation, and ovarian cancer growth; and raises the possibility of using antiplatelet reagents and complement inhibitors as novel synergisticanti-tumor reagents in ovarian cancer. Disclosures No relevant conflicts of interest to declare.

scholarly journals Overexpression of Pregnancy-Associated Plasma Protein-A in Ovarian Cancer Cells Promotes Tumor Growth in Vivo

Endocrinology ◽  
2011 ◽  
Vol 152 (4) ◽  
pp. 1470-1478 ◽  
Author(s):  
Henning B. Boldt ◽  
Cheryl A. Conover
Keyword(s):  
Ovarian Cancer ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Proteolytic Activity ◽  
Protein A ◽  
Ovarian Cancer Cells ◽  
Igf System ◽  
Tumorigenic Potential

Abstract Pregnancy-associated plasma protein-A (PAPP-A) is an important regulatory component of the IGF system. Through proteolysis of inhibitory IGF binding proteins (IGFBPs), PAPP-A acts as a positive modulator of local IGF signaling in a variety of biological systems. A role of IGF in the progression of several common forms of human cancer is now emerging, and therapeutic intervention of IGF receptor signaling is currently being explored. However, little is known about the activities of other components of the IGF system in relation to cancer. We hypothesized that PAPP-A acts to enhance tumor growth in vivo. To test this hypothesis, we overexpressed wild-type PAPP-A or a mutant PAPP-A with markedly reduced IGFBP protease activity in SKOV3 cells, a human ovarian carcinoma cell line with low tumorigenic potential. In vitro, SKOV3 clones with elevated PAPP-A expression (PAPP-A-1, PAPP-A-28) showed accelerated anchorage-independent growth in soft agar assays compared to clones overexpressing mutant PAPP-A (E483Q-1, E483Q-5) and vector controls. PAPP-A-28, with the highest PAPP-A expression and IGFBP proteolytic activity, also had markedly increased cell invasion through Matrigel. In vivo, we found significantly accelerated tumor growth rates of PAPP-A-overexpressing SKOV3 clones compared with mutant PAPP-A and controls. Investigation of angiogenesis indicated that overexpression of PAPP-A favored development of mature tumor vasculature and that tumor precursors of PAPP-A-28 in particular had a significantly higher degree of vascularization months before obvious tumor development. In conclusion, our data show that PAPP-A proteolytic activity enhances the tumorigenic potential of ovarian cancer cells and establish a novel tumor growth-promoting role of PAPP-A.

scholarly journals Targeting galectin-3 with a high-affinity antibody for inhibition of high-grade serous ovarian cancer and other MUC16/CA-125-expressing malignancies

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Marina Stasenko ◽  
Evan Smith ◽  
Oladapo Yeku ◽  
Kay J. Park ◽  
Ian Laster ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Cancer Therapeutics ◽  
Ca 125 ◽  
Ovarian Cancer Cells ◽  
Carbohydrate Binding ◽  
Matrigel Invasion ◽  
Galectin 3

AbstractThe lectin, galectin-3 (Gal3), has been implicated in a variety of inflammatory and oncogenic processes, including tumor growth, invasion, and metastasis. The interactions of Gal3 and MUC16 represent a potential targetable pathway for the treatment of MUC16-expressing malignancies. We found that the silencing of Gal3 in MUC16-expressing breast and ovarian cancer cells in vitro inhibited tumor cell invasion and led to attenuated tumor growth in murine models. We therefore developed an inhibitory murine monoclonal anti–Gal3 carbohydrate-binding domain antibody, 14D11, which bound human and mouse Gal3 but did not bind human Galectins-1, -7, -8 or -9. Competition studies and a docking model suggest that the 14D11 antibody competes with lactose for the carbohydrate binding pocket of Gal3. In MUC16-expressing cancer cells, 14D11 treatment blocked AKT and ERK1/2 phosphorylation, and led to inhibition of cancer cell Matrigel invasion. Finally, in experimental animal tumor models, 14D11 treatment led to prolongation of overall survival in animals bearing flank tumors, and retarded lung specific metastatic growth by MUC16 expressing breast cancer cells. Our results provide evidence that antibody based Gal3 blockade may be a viable therapeutic strategy in patients with MUC16-expressing tumors, supporting further development of human blocking antibodies against Gal3 as potential cancer therapeutics.

scholarly journals The role of Sox6 and Netrin-1 in ovarian cancer cell growth, invasiveness, and angiogenesis

Tumor Biology ◽  
2017 ◽  
Vol 39 (5) ◽  
pp. 101042831770550 ◽  
Author(s):  
Yi Li ◽  
Ming Xiao ◽  
Fangchun Guo
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Conditioned Medium ◽  
Umbilical Vein ◽  
Inhibitory Effect ◽  
Ovarian Cancer Cells ◽  
Human Umbilical Vein ◽  
Tumor Tissues

SOX6 plays important roles in cell proliferation, differentiation, and cell fate determination. It has been confirmed that SOX6 is a tumor suppressor and downregulated in various cancers, including esophageal squamous cell carcinoma, hepatocellular carcinoma, and chronic myeloid leukemia. Netrin-1 is highly expressed in various human cancers and acts as an anti-apoptotic and proangiogenic factor to drive tumorigenesis. The role of SOX6 and netrin-1 in regulating the growth of ovarian tumor cells still remains unclear. Real-time polymerase chain reaction and western blot were used to determine the SOX6 messenger RNA and protein levels, respectively, in ovarian cancer cells and tumor tissues. Stable transfection of SOX6 was conducted to overexpress SOX6 in PA-1 and SW626 cells. Cell viability was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Invasion of ovarian cancer cells and migration of human umbilical vein endothelial cells were confirmed by Transwell assays. To overexpress netrin-1, ovarian cancer cells with SOX6 restoration was transduced with netrin-1 lentiviral particles. PA-1 xenografts in a nude mice model were used to conduct in vivo evaluation of the role of SOX6 and its relationship with netrin-1 in tumor growth and angiogenesis. In this study, we found significantly reduced SOX6 levels in PA-1, SW626, SK-OV-3, and CaoV-3 ovarian cancer cell lines and human tumor tissues in comparison with normal human ovarian epithelial cells or matched non-tumor tissues. SOX6 overexpression by stable transfection dramatically inhibited proliferation and invasion of PA-1 and SW626 cells. Also, conditioned medium from PA-1 and SW626 cells with SOX6 restoration exhibited reduced ability to induce human umbilical vein endothelial cells migration and tube formation compared with conditioned medium from the cells with transfection control. Furthermore, an inverse relationship between SOX6 and netrin-1 expression was observed in PA-1 and SW626 cells. Overexpression of netrin-1 in ovarian cancer cells with forced SOX6 expression remarkably abrogated the inhibitory effect of SOX6 on proliferation, invasion of the cells, and tumor xenograft growth and vascularity in vivo. Human umbilical vein endothelial cell migration and tube formation were enhanced in the conditioned medium from the ovarian cancer cells transduced with netrin-1 lentivirus particles. Our observations revealed that SOX6 is a tumor suppressor in ovarian cancer cells, and SOX6 exerts an inhibitory effect on the proliferation, invasion, and tumor cell-induced angiogenesis of ovarian cancer cells, whereas nerin-1 plays an opposite role and its expression is inversely correlated with SOX6. Moreover, our findings suggest a new role of SOX6 and netrin-1 for understanding the progression of ovarian cancer and have the potential for the development of new diagnosis and treatment strategies for ovarian cancer.

Role of Rb Family in Vitamin D Receptor-Mediated Anti-Tumor Effects in Ovarian Cancer Cells.

2010 ◽  
pp. P1-9-P1-9
Author(s):  
J Tang ◽  
P Li ◽  
AKW Tse ◽  
SV Nicosia ◽  
X Zhang ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Vitamin D ◽  
Cancer Cells ◽  
Vitamin D Receptor ◽  
Ovarian Cancer Cells

Role of the TLR4-androgen receptor axis and genistein in taxol-resistant ovarian cancer cells

2020 ◽  
Vol 177 ◽  
pp. 113965
Author(s):  
Shang-Lang Huang ◽  
Ting-Chang Chang ◽  
Chuck C.K. Chao ◽  
Nian-Kang Sun
Keyword(s):  
Ovarian Cancer ◽  
Androgen Receptor ◽  
Cancer Cells ◽  
Ovarian Cancer Cells

scholarly journals The Role of Tumor-Associated Macrophages in the Progression and Chemoresistance of Ovarian Cancer

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1299 ◽  
Author(s):  
Marek Nowak ◽  
Magdalena Klink
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Immune Cells ◽  
Ovarian Cancer Cells ◽  
High Plasticity ◽  
Tumor Associated Macrophages ◽  
Survival Signaling ◽  
High Level ◽  
Stimulating Factor

Tumor-associated macrophages (TAMs) constitute the main population of immune cells present in the ovarian tumor microenvironment. These cells are characterized by high plasticity and can be easily polarized by colony-stimulating factor-1, which is released by tumor cells, into an immunosuppressive M2-like phenotype. These cells are strongly implicated in both the progression and chemoresistance of ovarian cancer. The main pro-tumoral function of M2-like TAMs is the secretion of a variety of cytokines, chemokines, enzymes and exosomes that reach microRNAs, directly inducing the invasion potential and chemoresistance of ovarian cancer cells by triggering their pro-survival signaling pathways. The M2-like TAMs are also important players in the metastasis of ovarian cancer cells in the peritoneum through their assistance in spheroid formation and attachment of cancer cells to the metastatic area—the omentum. Moreover, TAMs interplay with other immune cells, such as lymphocytes, natural killer cells, and dendritic cells, to inhibit their responsiveness, resulting in the development of immunosuppression. The detrimental character of the M2-like type of TAMs in ovarian tumors has been confirmed by a number of studies, demonstrating the positive correlation between their high level in tumors and low overall survival of patients.

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