Inhibition of vacuolar ATPase subunit in tumor cells delays tumor growth by decreasing the essential macrophage population in the tumor microenvironment

Oncogene ◽  
2015 ◽  
Vol 35 (8) ◽  
pp. 1058-1065 ◽  
Author(s):  
G K Katara ◽  
A Kulshrestha ◽  
M K Jaiswal ◽  
S Pamarthy ◽  
A Gilman-Sachs ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Vacuolar Atpase ◽  
Atpase Subunit ◽  
Macrophage Population

High-diluted thymulin on Ehrlich tumor growth in mice and the importance of tumor microenvironment

2021 ◽  
Vol 17 (3-4) ◽  
pp. 20-41
Author(s):  
Juliana Gimenez Amaral ◽  
Thayna Neves Cardoso ◽  
Aloísio Cunha De Carvalho ◽  
Cideli de Paula Coelho ◽  
Silvia Waisse ◽  
...  
Keyword(s):  
Immune Response ◽  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Spleen Cell ◽  
Tumor Cells ◽  
Caspase 3 ◽  
Tumor Growth Rate ◽  
Cell Populations ◽  
Ehrlich Tumor ◽  
Systemic Immune Response

Introduction: The aim of the present study was to describe different biological aspects of Ehrlich tumor in mice, such as body weight evolution, tumor growth rate, histological organization and systemic immune response after treatment with high-diluted thymulin (10-9 M, named 5CH). Methods: Tumor assessment was focused on macro- and microscopic aspects; parameters included occurrence of necrosis, embolism and tumor development, in addition to quantitative analysis of apoptosis (caspase-3), cell proliferation (Ki-67) and angiogenesis (vascular endothelial growth factor - VEGF) by means of specific immunohistochemistry markers. Spleen cell populations were evaluated by flow cytometry analysis. Results: Mice treated with thymulin 5CH exhibited changes in the tumor microenvironment, such as reduced micro-embolism incidence and cytokeratin expression, with increased caspase-3 expression in the tumor cells. These findings indicate some apoptotic activity by the tumor cells induced by the treatment, even though no reduction of the macroscopic tumor mass occurred. No changes in the systemic immune response were detected, as the balance among spleen cell populations remained unchanged. Conclusions: The results indicate that treatment of mice bearing Ehrlich tumor with thymulin 5CH induces some specific changes in the tumor environment. However, it did not influence systemic immunity parameters. Adjuvant use of thymulin 5CH in oncological clinical practice is still a matter of discussion.

Platelet Depletion Reduces Tumor Hypoxia and Metastasis Mediated by Met Signaling Pathway

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3321-3321
Author(s):  
Rong Li ◽  
Meiping Ren ◽  
Ni Chen ◽  
Mao Luo ◽  
Jianbo Wu
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Primary Tumor ◽  
Tumor Hypoxia ◽  
Hemoglobin Content ◽  
Melanoma Cancer ◽  
And Control ◽  
Platelet Depletion

Abstract Abstract 3321 Platelets play a fundamental role in maintaining hemostasis and have been shown to participate in hemorrhagic metastasis. However, the role of platelets in the tumor growth, angiogenesis, and metastasis initiation remains undefined. The B16/F10 melanoma cancer cells model of metastasis and the Lewis lung carcinoma (LLC) spontaneous pulmonary metastasis model were used for this purpose. Using induction of thrombocytopenia, primary tumor growth was monitored and every 3 days anti-GPIbα or rat IgG injections were initiated when tumor reached ∼500mm3and continued until tumor reached to 3 weeks. We showed that platelet depletion had no change in tumor growth but reduced metastasis. Platelet depletion significantly increased pericyte coverage and reduced vascular density compared with control mice. We evaluated the ratio of fluorescence intensities within the plasma and tumor following injection of mice with FITC-dextran. We found that the FITC-dextran was similarly deposited into the tumor tissue in either platelet-depleted or control mice, indicating that tumor vessel perfusion did not differ in either platelet-depleted or control mice. To further gain insight into the molecular mechanisms associated with reduced metastasis resulting from platelet depletion, we assessed hypoxia levels by examining pimonidazole adduct formation in the tumors of platelet-depleted and control mice and found decreased hypoxic levels in the platelet-depleted tumors. In addition, expression of the hypoxia-inducible transcription factor HIF-1α was also significantly reduced in the tumors of platelet-depleted mice. Tumor hypoxia is strongly associated with deposition of hemoglobin. We measured the intratumor hemoglobin content, reflecting the level of erythrocytes extravasation. The hemoglobin content in the tumors of mice with platelet-depletion was significantly higher than that of control mice (172.11 ± 20.2 g/L/g Vs. 110.28 ± 12.4 g/L/g, p<0.05) Based on the known induction effects of hypoxia and cancer invasiveness on the expression and activation of the proinvasive tyrosine kinase receptor Met, we analyzed total protein and tyrosine phosphorylation levels of Met in both platelet-depleted and control mice. Western blotting analysis revealed that platelet-depletion caused a significantly decrease of both total Met and phosph-Met in tumors when compared to tumors from control mice. To evaluate intratumoral growth factor level, microdialysis was performed after 3 weeks and there was a significant decrease of extracellular VEGF and TNF-β in platelet depletion mice compared with control mice. Recent studies demonstrated that abundant platelets were detected in the tumor microenvironment apart from the vasculature. Based on the finding platelets in contact with tumor cells outside the bloodstream, we examined the functional effects of co-implantation of B16/F10 tumor cells with platelets on tumor progression and metastasis. B16/F10 melanoma cancer cells were implanted into back of wild type mice. During a 3-weeks growth, co-implantation of B16/F10 with platelets not only led to promoted tumor volume (3968 ± 296 mm3Vs. 2956 ± 180 mm3, p<0.05) and weight (5.529 ± 0.35 g Vs. 3.943 ± 0.738 g, p<0.05 ) compared with B16/F10 alone implantation, but also led to an increase in metastasis. Furthermore, in vitro co-culture of B16/F10 cancer cells with platelets showed a significant increase in B16/F10 cancer cells invasion compared with B16/F10 cancer cells alone. In conclusion, our findings demonstrate for the first time that platelets play a critical role in the initiation of tumor metastasis. Moreover, our findings suggest that platelets within the primary tumor microenvironment are likely involved in tumor progression and metastasis. Disclosures: No relevant conflicts of interest to declare.

scholarly journals SAT-129 Interactions Between Macrophages and Cancer Stem-Like Cells Promote Mammary Tumor Angiogenesis Under Obesity

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Lauren Hillers-Ziemer ◽  
Rachel McMahon ◽  
Margaret Hieptas ◽  
Gretchen Paderta ◽  
Jessica McCready ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Tumor Angiogenesis ◽  
Tumor Necrosis ◽  
Health Concern ◽  
Vitro Assay ◽  
Aggressive Tumors

Abstract Obesity is a growing health concern worldwide and increases the incidence of multiple types of cancer, including breast cancer. Obese breast cancer patients often develop more aggressive tumors than lean patients and have increased risk for metastasis, tumor recurrence and mortality. Here, we sought to address how obesity alters the biology of breast cancer to promote aggressive tumors. To induce obesity, we fed mice either a control diet (CD) or high fat diet (HFD) for 16 weeks, then transplanted Met-1 tumor cells into mammary fat pads and monitored tumor growth. At end stage, tumors from HFD-fed mice were significantly larger than tumors from CD-fed mice, suggesting obesity promotes tumor growth. To investigate how obesity promotes tumor aggression, we dissociated the tumors from CD- and HFD-fed mice and plated isolated tumor cells in tumorsphere and invasion assays to test for cells with cancer stem-like cell (CSC) properties. Tumor cells from HFD-fed mice demonstrated increased tumorsphere formation and increased capacity for invasion compared to tumor cells from CD-fed mice, suggesting that obesity selects for tumor cells with CSC properties. Next, to address how obesity impacts the tumor microenvironment, we evaluated tumor necrosis and blood vessel formation through CD31 staining. Tumors from HFD-fed mice had significantly less necrosis and greater CD31 staining than those from CD-fed mice, suggesting that obesity promotes tumor angiogenesis. Since obesity promotes chronic, macrophage-driven inflammation within adipose tissue of the mammary gland, we stained tumors for the macrophage marker, F4/80. As with obese mammary glands, tumors from HFD-fed mice had significantly greater macrophage recruitment than tumors from CD-fed mice, together suggesting that obesity alters the tumor microenvironment. To determine how obesity stimulates tumor angiogenesis, we performed an in vitro assay by culturing dissociated tumor cells from HFD or CD-fed mice alone or with macrophages. Conditioned media (CM) isolated from tumor cells from HFD-fed mice cultured with macrophages enhanced the ability of endothelial cells to form networks in vitro. In contrast, CM from HFD tumor cells alone, macrophages alone, or those from CD-fed mice did not promote network formation. Together, these results suggest that cooperation between macrophages and tumor cells from HFD-fed mice promotes angiogenesis. Next, to investigate how macrophages and tumor cells interacting in obesity, we depleted macrophages using anti-F4/80 antibodies in CD-fed and HFD-fed tumor-bearing mice. In HFD-fed mice, macrophage depletion significantly reduced tumor volume and CD31 staining while increasing tumor necrosis compared to controls. Obesity promotes interactions between tumor cells and macrophages to enhance tumor angiogenesis and progression.

732 Chemerin reactivates PTEN and suppresses PD-L1 in tumor cells via a novel CMKRL1-mediated pathway

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A776-A776
Author(s):  
Russell Pachynski ◽  
Keith Rennier ◽  
Woo Jae Shin ◽  
Ethan Krug ◽  
Gurpal Virdi ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Human Tumor ◽  
In Vivo Studies ◽  
Cell Phenotype ◽  
Immune Effector ◽  
First Time

BackgroundChemokines and chemoattractants play critical roles in trafficking that help regulate leukocyte infiltrates in the tumor microenvironment. Chemokines/chemoattractants can also modulate tumor cell phenotype and function, as tumor cells express functional receptors for these agents. Chemerin (retinoic acid receptor responder 2, RARRES2) is an endogenous leukocyte chemoattractant that recruits innate immune cells through its receptor, CMKLR1. RARRES2 is widely expressed in nonhematopoietic tissues and often downregulated across multiple tumor types compared with normal tissue. We and others have shown that augmenting chemerin in the tumor microenvironment significantly suppresses tumor growth, in part, by immune effector cell recruitment. As chemerin has various roles outside of leukocyte trafficking (eg adipocyte differentiation and metabolic processes), we hypothesized that it may have additional, tumor-intrinsic effects.MethodsWe investigated the effect of exogenous chemerin on human prostate and sarcoma tumor lines. Key signaling pathway components were elucidated using qPCR, Western blotting, siRNA knockdown, and specific inhibitors. Functional consequences of chemerin treatment were evaluated using in vitro and in vivo studies.ResultsWe show for the first time that human tumors exposed to exogenous chemerin significantly upregulate PTEN expression/activity, and concomitantly suppress programmed death ligand-1 (PD-L1) expression. CMKLR1 knockdown abrogated chemerin- induced PTEN and PD-L1 modulation, revealing a novel CMKLR1/PTEN/PD-L1 signaling cascade. Targeted inhibitors suggest that signaling occurs through the PI3K/AKT/mTOR pathway. We found that chemerin treatment significantly reduced tumor migration, while significantly increasing T-cell–mediated cytotoxicity. Chemerin treatment was as effective as both PD-L1 knockdown and the anti–PD-L1 antibody atezolizumab in augmenting T cell mediated tumor lysis. Forced expression of chemerin in human DU145 prostate tumors significantly suppressed in vivo tumor growth, significantly increasing PTEN and decreasing PD-L1 expression. Primary prostate tumor cultures that were treated with recombinant chemerin showed significant increases in PTEN and decreases in PD-L1 expression compared to controls. Lastly, analyses of clinical trial data from human metastatic prostate cancer patients receiving treatment with ipilimumab (NCT02113657) showed higher tumoral levels of RARRES2 expression correlated with higher levels of PTEN, higher effector immune cell (eg cytotoxic T cells, NK cells) signatures, and improved clinical outcomes, suggesting a strategy to augment chemerin/RARRES2 levels in tumors may improve responses to immunotherapy.ConclusionsCollectively, our data show for the first time a novel link between chemerin, PTEN, and PD-L1 in human tumor lines. These results show that chemerin – in addition to its ability to suppress tumor growth by recruitment of immune effector cells, may also have a role in improving T-cell–mediated immunotherapies through favorable modulation of PTEN and PD-L1.

The Heparanase Inhibitor SST0001 Is a Potent Inhibitor of Myeloma Growth In Vivo

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 246-246 ◽  
Author(s):  
Yang Yang ◽  
Joseph P. Ritchie ◽  
Telisha Swain ◽  
Annamaria Naggi ◽  
Giangiacomo Torri ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Heparan Sulfate ◽  
Cell Line ◽  
Tumor Cells ◽  
Subcutaneous Injection ◽  
Scid Mice ◽  
Rpmi 8226

Abstract Heparanase (HPSE) is an enzyme that cleaves heparan sulfate (HS) chains of proteoglycans. Work by us and others has demonstrated that heparanase promotes the growth and metastasis of many types of tumors, including multiple myeloma (MM). Heparanase expression is rare in normal tissue but becomes evident in many human tumors, making it a viable target for cancer therapy. SST0001, a chemically modified heparin that is 100% N-acetylated and 25% glycol-split, dramatically inhibits heparanase activity. SST0001 lacks anticoagulant activity and thus can be administered at relatively high doses in vivo. We previously reported that delivery of SST0001 by Alzet osmotic pumps to SCID mice potently inhibited growth of subcutaneous tumors formed by CAG human myeloma cells. In the present studies, we further tested the effects of SST0001 against additional MM cell lines, using alternative routes of drug delivery in two different animal models. Ten days after subcutaneous injection of either MM.1S or RPMI 8226 tumor cells, mice were treated for 28 days using Alzet pumps delivering 30 mg/kg/day of SST0001. Results showed that, compared to PBS control, MM.1S and RPMI-8226 tumors in SST0001-treated mice were reduced by 50% and 51%, respectively. In a separate experiment, delivery of SST0001 by distant subcutaneous injection inhibited tumor growth by 77% in comparison to controls. In the SCID-hu model, in which CAG cells were implanted directly into human bones engrafted in SCID mice, SST0001 also significantly inhibited tumor growth as measured by human immunoglobulin kappa light chain in murine sera (1055 ± 295 ng/ml in PBS-treated mice vs 155 ± 295 ng/ml in SST0001- treated mice (P &lt;0.003)). These data demonstrate that SST0001 is a strong inhibitor of MM growth in vivo, even when tumors grow within the bone microenvironment and that the effect of SST0001 is not cell-line specific. We did not observe any adverse side effects in animals, even at doses as high as 120 mg/kg/day. To determine the mechanism of action of SST0001, we examined several pharmacodynamic parameters. Immunohistochemistry demonstrated that SST0001 treatment significantly reduced microvessel density of tumors as compared to controls (99% in CAG and 54% in RPMI-8226 tumors). In addition, SST0001 treatment blocked HGF expression (CAG, RPMI 8226 and MM.1S tumors) and inhibited VEGF expression in CAG tumors but not RPMI 8226 and MM.1S tumors. Moreover, a series of in vitro experiments, using the CAG MM cell line and human umbilical vein endothelial cells (HUVEC), were performed. Unlike its strong antitumor effect in vivo, SST0001 only slightly inhibited CAG cell proliferation, cell cycle and growth factor signaling in vitro, suggesting that the compound does not have a direct cytotoxic effect on tumor cells. Since blood vessels are an important element of the tumor microenvironment and angiogenic endothelium in tumors also expresses high levels of heparan sulfate proteoglycans and heparanase, we assessed the effects of SST0001 on HUVEC cells. In contrast with results on CAG MM cells, SST0001 treatment showed a strong inhibition on HUVEC proliferation (46%, MTT assay), dramatically blocked the phosphorylation of ERK stimulated by HS-binding growth factors (HGF, VEGF, HDGF and EGF), blocked the Akt pathway of HGF signaling in HUVECs and inhibited HUVEC tube formation, stimulated by HGF and VEGF. Based on these results, we conclude that SST0001 strongly inhibits the growth of myeloma tumors in vivo by targeting the tumor microenvironment, including a significant inhibition of tumor angiogenesis. Because of its unique target site in the tumor microenvironment, we predict that the combination of SST0001 with conventional tumor cell-targeting chemotherapeutic drugs will greatly improve patient outcome in MM.

scholarly journals Cancer: An Oxidative Crosstalk between Solid Tumor Cells and Cancer Associated Fibroblasts

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Alessandro Arcucci ◽  
Maria Rosaria Ruocco ◽  
Giuseppina Granato ◽  
Anna Maria Sacco ◽  
Stefania Montagnani
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Tumor Progression ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Critical Role ◽  
Metabolic Reprogramming ◽  
Antioxidant Systems ◽  
Activation Process ◽  
Cancer Associated Fibroblasts

Redox balance is associated with the regulation of several cell signalling pathways and functions. In fact, under physiological conditions, cells maintain a balance between oxidant and antioxidant systems, and reactive oxygen species (ROS) can act as second messengers to regulate cell proliferation, cell death, and other physiological processes. Cancer tissues usually contain higher levels of ROS than normal tissues, and this ROS overproduction is associated with tumor development. Neoplastic tissues are very heterogeneous systems, composed of tumor cells and microenvironment that has a critical role in tumor progression. Cancer associated fibroblasts (CAFs) represent the main cell type of tumor microenvironment, and they contribute to tumor growth by undergoing an irreversible activation process. It is known that ROS can be transferred from cancer cells to fibroblasts. In particular, ROS affect the behaviour of CAFs by promoting the conversion of fibroblasts to myofibroblasts that support tumor progression and dissemination. Furthermore, the wrecking of redox homeostasis in cancer cells and tumor microenvironment induces a metabolic reprogramming in tumor cells and cancer associated fibroblasts, giving advantage to cancer growth. This review describes the role of ROS in tumor growth, by focusing on CAFs activation and metabolic interactions between cancer cells and stromal fibroblasts.

scholarly journals TMIC-20. ELIMINATION OF SENESCENT ASTROCYTES IN THE BRAIN TUMOR MICROENVIRONMENT ATTENUATES GLIOBLASTOMA RECURRENCE AFTER RADIOTHERAPY

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi251-vi251
Author(s):  
Eliot Fletcher-Sananikone ◽  
Bipasha Mukherjee ◽  
Sandeep Burma
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Neutralizing Antibodies ◽  
Glioma Cells ◽  
Cell Types ◽  
Normal Brain ◽  
High Doses

Abstract Glioblastomas (GBM) are treated with high doses of ionizing radiation (IR) yet these tumors inevitably recur, and the recurrent tumors are highly therapy resistant. During GBM therapy, the surrounding brain tissue is irradiated along with the tumor. IR induces senescence in multiple cell types, and senescent stromal cells are known to promote the growth of neighboring tumor cells by secreting cytokines which create a senescence-associated secretory phenotype (SASP). We hypothesize that IR-induced senescence of normal brain cells in the tumor microenvironment is a powerful driver of GBM recurrence. We intra-cranially irradiated C57BL/6J mice, and found evidence of widespread senescence, with the astrocytic population being highly susceptible. Genomic analyses of irradiated brains revealed an altered transcriptomic profile which included upregulation of CDKN1A (p21), a key enforcer of senescence, and increased expression of SASP proteins including HGF, the ligand for the RTK Met. We orthotopically implanted mock-irradiated or irradiated mice with a limiting number of syngeneic glioma cells. Pre-irradiation of mouse brains resulted in a striking increase in tumor growth and invasion driven by Met activation in the tumor cells. Importantly, irradiated p21-/- mouse brains did not exhibit SASP and failed to promote tumor growth. Irradiated primary astrocytes underwent senescence in vitro and promoted the migration of glioma cells, and this could be attenuated with HGF-neutralizing antibodies or by the Met inhibitor Crizotinib. These findings indicate that SASP factors (like HGF) in the irradiated brain microenvironment could drive GBM recurrence after radiotherapy via the activation of RTKs (like MET) in the tumor cells. Significantly, we found that senolytic drugs can selectively kill senescent astrocytes both in vitro and in vivo resulting in attenuated growth of glioma cells. These results are of great translational significance as they indicate that adjuvant therapy with senolytic drugs might attenuate GBM recurrence after radiotherapy.

scholarly journals Cancer-Associated Fibroblasts in Conversation with Tumor Cells in Endometrial Cancers: A Partner in Crime

2021 ◽  
Vol 22 (17) ◽  
pp. 9121
Author(s):  
De Pradip ◽  
Aske Jennifer ◽  
Dey Nandini
Keyword(s):  
Drug Resistance ◽  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Cross Talk ◽  
Critical Role ◽  
Immune Surveillance ◽  
Endometrial Cancers

A tumor cell carrying characteristic genomic alteration(s) exists within its host’s microenvironment. The tumor microenvironment (TME) renders holistic support to the tumor via cross-talk between tumor cells and three components of TME, immune components, vascular components, and fibroblast components. The tempero-spatial interaction of tumor cells with its microenvironment is the deterministic factor for tumor growth, progression, resistance to therapy, and its outcome in clinics. TME (1) facilitates proliferation, and the ensuing metastasis-associated phenotypes, (2) perturbs immune surveillance and supports tumor cells in their effort to evade immune recognition, and (3) actively participates in developing drug-induced resistance in cancer cells. Cancer-Associated Fibroblast (CAF) is a unique component of TME. CAF is the host mesenchyme immediately surrounding the tumor cells in solid tumors. It facilitates tumor growth and progression and participates in developing drug resistance in tumor cells by playing a critical role in all the ways mentioned above. The clinical outcome of a disease is thus critically contributed to by the CAF component of TME. Although CAFs have been identified historically, the functional relevance of CAF-tumor cell cross-talk and their influence on angiogenic and immune-components of TME are yet to be characterized in solid tumors, especially in endometrial cancers. Currently, the standard of care for the treatment of endometrial cancers is primarily guided by therapies directed towards the disease’s tumor compartment and immune compartments. Unfortunately, in the current state of therapies, a complete response (CR) to the therapy is still limited despite a more commonly achieved partial response (PR) and stable disease (SD) in patients. Acknowledging the limitations of the current sets of therapies based on only the tumor and immune compartments of the disease, we sought to put forward this review based on the importance of the cross-talk between CAF of the tumor microenvironment and tumor cells. The premise of the review is to recognize the critical role of CAF in disease progression. This manuscript presents a systemic review of the role of CAF in endometrial cancers. We critically interrogated the active involvement of CAF in the tumor compartment of endometrial cancers. Here we present the functional characteristics of CAF in the context of endometrial cancers. We review (1) the characteristics of CAF, (2) their evolution from being anti-tumor to pro-tumor, (3) their involvement in regulating growth and several metastasis-associated phenotypes of tumor cells, (4) their participation in perturbing immune defense and evading immune surveillance, and (5) their role in mediating drug resistance via tumor-CAF cross-talk with particular reference to endometrial cancers. We interrogate the functional characteristics of CAF in the light of its dialogue with tumor cells and other components of TME towards developing a CAF-based strategy for precision therapy to supplement tumor-based therapy. The purpose of the review is to present a new vision and initiate a thought process which recognizes the importance of CAF in a tumor, thereby resulting in a novel approach to the design and management of the disease in endometrial cancers.

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