scholarly journals Characterizing Endocrine Status, Tumor Hypoxia and Immunogenicity for Therapy Success in Epithelial Ovarian Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Madison Pereira ◽  
Kathy Matuszewska ◽  
Colin Jamieson ◽  
Jim Petrik
Keyword(s):  
Ovarian Cancer ◽  
Tumor Microenvironment ◽  
Epithelial Ovarian Cancer ◽  
Tumor Heterogeneity ◽  
Tumor Hypoxia ◽  
Therapy Response ◽  
Treatment Resistance ◽  
Malignant Ascites ◽  
Response To Therapy ◽  
Vascular Density

Epithelial ovarian cancer is predominantly diagnosed at advanced stages which creates significant therapeutic challenges. As a result, the 5-year survival rate is low. Within ovarian cancer, significant tumor heterogeneity exists, and the tumor microenvironment is diverse. Tumor heterogeneity leads to diversity in therapy response within the tumor, which can lead to resistance or recurrence. Advancements in therapy development and tumor profiling have initiated a shift from a “one-size-fits-all” approach towards precision patient-based therapies. Here, we review aspects of ovarian tumor heterogeneity that facilitate tumorigenesis and contribute to treatment failure. These tumor characteristics should be considered when designing novel therapies or characterizing mechanisms of treatment resistance. Individual patients vary considerably in terms of age, fertility and contraceptive use which innately affects the endocrine milieu in the ovary. Similarly, individual tumors differ significantly in their immune profile, which can impact the efficacy of immunotherapies. Tumor size, presence of malignant ascites and vascular density further alters the tumor microenvironment, creating areas of significant hypoxia that is notorious for increasing tumorigenesis, resistance to standard of care therapies and promoting stemness and metastases. We further expand on strategies aimed at improving oxygenation status in tumors to dampen downstream effects of hypoxia and set the stage for better response to therapy.

scholarly journals Bipolar Tumor-Associated Macrophages in Ovarian Cancer as Targets for Therapy

Cancers ◽  
2018 ◽  
Vol 10 (10) ◽  
pp. 366 ◽  
Author(s):  
Vijayalaxmi Gupta ◽  
Fiona Yull ◽  
Dineo Khabele
Keyword(s):  
Ovarian Cancer ◽  
Tumor Microenvironment ◽  
Epithelial Ovarian Cancer ◽  
Tumor Cells ◽  
Peritoneal Metastasis ◽  
Gynecological Cancer ◽  
Malignant Ascites ◽  
Tumor Associated Macrophages ◽  
Fatal Disease ◽  
Cancer Tumor

Ovarian cancer, a rare but fatal disease, has been a challenging area in the field of gynecological cancer. Ovarian cancer is characterized by peritoneal metastasis, which is facilitated by a cross-talk between tumor cells and other cells in the tumor microenvironment (TME). In epithelial ovarian cancer, tumor-associated macrophages (TAMs) constitute over 50% of cells in the peritoneal TME and malignant ascites, and are potential targets for therapy. Here, we review the bipolar nature of TAMs and the evolving strategies to target TAMs in ovarian cancer.

scholarly journals Clinical significance of circulating tumor cell related markers in patients with epithelial ovarian cancer before and after adjuvant chemotherapy

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Meysam Yousefi ◽  
Sara Rajaie ◽  
Vahideh Keyvani ◽  
Somayeh Bolandi ◽  
Malihe Hasanzadeh ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Adjuvant Chemotherapy ◽  
Epithelial Ovarian Cancer ◽  
Clinical Significance ◽  
Therapy Response ◽  
Serum Levels ◽  
Circulating Tumor Cell ◽  
Tumor Stage ◽  
Disease Stage ◽  
Before And After

AbstractCirculating tumor cells (CTCs) have recently been considered as new prognostic and diagnostic markers for various human cancers; however, their significance in epithelial ovarian cancer (EOC) remains to be elucidated. In this study, using quantitative real-time PCR, we evaluated the expression of EPCAM, MUC1, CEA, HE4 and CA125 mRNAs, as putative markers of CTCs, in the blood of 51 EOC patients before and/or after adjuvant chemotherapy. Our results demonstrated that, before chemotherapy, the expression of EPCAM, MUC1, CEA and HE4 mRNAs were correlated to each other. CEA expression was correlated with tumor stage (r = 0.594, p = 0.000) before chemotherapy, whereas its expression after chemotherapy was correlated with serum levels of CA125 antigen (r = 0.658, p = 0.000). HE4 mRNA showed the highest sensitivity both before and after chemotherapy (82.98% and 85.19%, respectively) and the persistence of this marker after chemotherapy was associated with advanced disease stage. The expression of CA125 mRNA had negative correlation with the other markers and with tumor stage and therapy response (evaluated by the measurement of serum CA125 antigen). Collectively, our results indicated a better clinical significance of tumor-specific markers (CEA and HE4 mRNAs) compared to epithelial-specific markers (EPCAM and MUC1 mRNAs).

scholarly journals MIXTURE: an improved algorithm for immune tumor microenvironment estimation based on gene expression data

2019 ◽  
Author(s):  
Elmer A. Fernández ◽  
Yamil D. Mahmoud ◽  
Florencia Veigas ◽  
Darío Rocha ◽  
Mónica Balzarini ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Immune Cell ◽  
Therapy Response ◽  
Cell Types ◽  
Gene Signature ◽  
Response To Therapy ◽  
Support Vector ◽  
Data Sets ◽  
Cell Type ◽  
Before And After

AbstractRNA sequencing has proved to be an efficient high-throughput technique to robustly characterize the presence and quantity of RNA in tumor biopsies at a given time. Importantly, it can be used to computationally estimate the composition of the tumor immune infiltrate and to infer the immunological phenotypes of those cells. Given the significant impact of anti-cancer immunotherapies and the role of the associated immune tumor microenvironment (ITME) on its prognosis and therapy response, the estimation of the immune cell-type content in the tumor is crucial for designing effective strategies to understand and treat cancer. Current digital estimation of the ITME cell mixture content can be performed using different analytical tools. However, current methods tend to over-estimate the number of cell-types present in the sample, thus under-estimating true proportions, biasing the results. We developed MIXTURE, a noise-constrained recursive feature selection for support vector regression that overcomes such limitations. MIXTURE deconvolutes cell-type proportions of bulk tumor samples for both RNA microarray or RNA-Seq platforms from a leukocyte validated gene signature. We evaluated MIXTURE over simulated and benchmark data sets. It overcomes competitive methods in terms of accuracy on the true number of present cell-types and proportions estimates with increased robustness to estimation bias. It also shows superior robustness to collinearity problems. Finally, we investigated the human immune microenvironment of breast cancer, head and neck squamous cell carcinoma, and melanoma biopsies before and after anti-PD-1 immunotherapy treatment revealing associations to response to therapy which have not seen by previous methods.

scholarly journals The Tumor Microenvironment of Epithelial Ovarian Cancer and Its Influence on Response to Immunotherapy

Cancers ◽  
2018 ◽  
Vol 10 (8) ◽  
pp. 242 ◽  
Author(s):  
Galaxia Rodriguez ◽  
Kristianne Galpin ◽  
Curtis McCloskey ◽  
Barbara Vanderhyden
Keyword(s):  
Ovarian Cancer ◽  
Tumor Microenvironment ◽  
Epithelial Ovarian Cancer ◽  
B Lymphocytes ◽  
Immune Cells ◽  
Ovarian Cancer Cell ◽  
Cell Types ◽  
Therapeutic Approaches ◽  
Mutational Burden ◽  
Tumor Mutational Burden

Immunotherapy as a treatment for cancer is a growing field of endeavor but reports of success have been limited for epithelial ovarian cancer. Overcoming the challenges to developing more effective therapeutic approaches lies in a better understanding of the factors in cancer cells and the surrounding tumor microenvironment that limit response to immunotherapies. This article provides an overview of some ovarian cancer cell features such as tumor-associated antigens, ovarian cancer-derived exosomes, tumor mutational burden and overexpression of immunoinhibitory molecules. Moreover, we describe relevant cell types found in epithelial ovarian tumors including immune cells (T and B lymphocytes, Tregs, NK cells, TAMs, MDSCs) and other components found in the tumor microenvironment including fibroblasts and the adipocytes in the omentum. We focus on how those components may influence responses to standard treatments or immunotherapies.

scholarly journals The Crowded Crosstalk between Cancer Cells and Stromal Microenvironment in Gynecological Malignancies: Biological Pathways and Therapeutic Implication

2019 ◽  
Vol 20 (10) ◽  
pp. 2401 ◽  
Author(s):  
Rosalba De Nola ◽  
Alessio Menga ◽  
Alessandra Castegna ◽  
Vera Loizzi ◽  
Girolamo Ranieri ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cervical Cancer ◽  
Tumor Microenvironment ◽  
Epithelial Ovarian Cancer ◽  
Cancer Cells ◽  
T Regulatory Cells ◽  
Tumor Infiltrating Lymphocytes ◽  
Estrogen Receptor Α ◽  
Biological Pathways ◽  
Cell Subpopulation

The tumor microenvironment plays a pillar role in the progression and the distance dissemination of cancer cells in the main malignancies affecting women—epithelial ovarian cancer, endometrial cancer and cervical cancer. Their milieu acquires specific properties thanks to intense crosstalk between stromal and cancer cells, leading to a vicious circle. Fibroblasts, pericytes, lymphocytes and tumor associated-macrophages orchestrate most of the biological pathways. In epithelial ovarian cancer, high rates of activated pericytes determine a poorer prognosis, defining a common signature promoting ovarian cancer proliferation, local invasion and distant spread. Mesenchymal cells also release chemokines and cytokines under hormonal influence, such as estrogens that drive most of the endometrial cancers. Interestingly, the architecture of the cervical cancer milieu is shaped by the synergy of high-risk Human Papilloma Virus oncoproteins and the activity of stromal estrogen receptor α. Lymphocytes represent a shield against cancer cells but some cell subpopulation could lead to immunosuppression, tumor growth and dissemination. Cytotoxic tumor infiltrating lymphocytes can be eluded by over-adapted cancer cells in a scenario of immune-tolerance driven by T-regulatory cells. Therefore, the tumor microenvironment has a high translational potential offering many targets for biological and immunological therapies.

scholarly journals Malignant Ascites in Ovarian Cancer: Cellular, Acellular, and Biophysical Determinants of Molecular Characteristics and Therapy Response

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4318
Author(s):  
Brittany P. Rickard ◽  
Christina Conrad ◽  
Aaron J. Sorrin ◽  
Mustafa Kemal Ruhi ◽  
Jocelyn C. Reader ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Biology ◽  
Metastatic Cancer ◽  
Treatment Options ◽  
Therapy Response ◽  
Therapy Resistance ◽  
Malignant Ascites ◽  
Molecular Characteristics ◽  
The Impact

Ascites refers to the abnormal accumulation of fluid in the peritoneum resulting from an underlying pathology, such as metastatic cancer. Among all cancers, advanced-stage epithelial ovarian cancer is most frequently associated with the production of malignant ascites and is the leading cause of death from gynecologic malignancies. Despite decades of evidence showing that the accumulation of peritoneal fluid portends the poorest outcomes for cancer patients, the role of malignant ascites in promoting metastasis and therapy resistance remains poorly understood. This review summarizes the current understanding of malignant ascites, with a focus on ovarian cancer. The first section provides an overview of heterogeneity in ovarian cancer and the pathophysiology of malignant ascites. Next, analytical methods used to characterize the cellular and acellular components of malignant ascites, as well the role of these components in modulating cell biology, are discussed. The review then provides a perspective on the pressures and forces that tumors are subjected to in the presence of malignant ascites and the impact of physical stress on therapy resistance. Treatment options for malignant ascites, including surgical, pharmacological and photochemical interventions are then discussed to highlight challenges and opportunities at the interface of drug discovery, device development and physical sciences in oncology.

scholarly journals Association of Soluble B7-H4 and Circulating Tumor Cells in Blood of Advanced Epithelial Ovarian Cancer Patients

2021 ◽  
Vol 11 ◽  
Author(s):  
Pawel Mach ◽  
Rainer Kimmig ◽  
Sabine Kasimir-Bauer ◽  
Paul Buderath
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Survival Data ◽  
Liquid Biopsy ◽  
Therapy Response ◽  
Predictive Biomarkers ◽  
Prognostic Biomarkers ◽  
Immune Checkpoints

IntroductionEpithelial ovarian cancer (EOC) is the deadliest gynecologic malignancy worldwide. Reliable predictive biomarkers are urgently needed to estimate the risk of relapse and to improve treatment management. Soluble immune-checkpoints in EOC are promising molecules serving as prognostic biomarkers accessible via liquid biopsy. We thus, aimed at elucidating the role of sB7-H4 in EOC.Material and MethodsWe analyzed soluble serum B7-H4 (sB7-H4) using ELISA and circulating tumor cells (CTCs) in blood applying the AdnaTest OvarianCancer in 85 patients suffering from advanced EOC. Findings were correlated with clinical parameters as well as survival data.ResultssB7-H4 was detectable in 14.1% patients, CTCs in 32.9% patients and simultaneous presence of CTCs and sB7-H4 was found in 7% patients, respectively. Although no association between sB7-H4 and CTC could be documented, each of them served as independent predictive factors for overall survival (OS).ConclusionsB7-H4 and CTCs are independent prognostic biomarkers for impaired survival in EOC. As they are easily accessible via liquid biopsy, they may be of potential benefit for the prediction of therapy response and survival for EOC patients.

scholarly journals Blockade of the CD93 pathway normalizes tumor vasculature to facilitate drug delivery and immunotherapy

2021 ◽  
Vol 13 (604) ◽  
pp. eabc8922
Author(s):  
Yi Sun ◽  
Wei Chen ◽  
Robert J. Torphy ◽  
Sheng Yao ◽  
Gefeng Zhu ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Tumor Microenvironment ◽  
Immune Cell ◽  
Vascular Dysfunction ◽  
Tumor Hypoxia ◽  
Tumor Vasculature ◽  
Poor Response ◽  
Response To Therapy ◽  
Mouse Tumor ◽  
Programmed Death

The immature and dysfunctional vascular network within solid tumors poses a substantial obstacle to immunotherapy because it creates a hypoxic tumor microenvironment that actively limits immune cell infiltration. The molecular basis underpinning this vascular dysfunction is not fully understood. Using genome-scale receptor array technology, we showed here that insulin-like growth factor binding protein 7 (IGFBP7) interacts with its receptor CD93, and we subsequently demonstrated that this interaction contributes to abnormal tumor vasculature. Both CD93 and IGFBP7 were up-regulated in tumor-associated endothelial cells. IGFBP7 interacted with CD93 via a domain different from multimerin-2, the known ligand for CD93. In two mouse tumor models, blockade of the CD93/IGFBP7 interaction by monoclonal antibodies promoted vascular maturation to reduce leakage, leading to reduced tumor hypoxia and increased tumor perfusion. CD93 blockade in mice increased drug delivery, resulting in an improved antitumor response to gemcitabine or fluorouracil. Blockade of the CD93 pathway triggered a substantial increase in intratumoral effector T cells, thereby sensitizing mouse tumors to immune checkpoint therapy. Last, analysis of samples from patients with cancer under anti–programmed death 1/programmed death-ligand 1 treatment revealed that overexpression of the IGFBP7/CD93 pathway was associated with poor response to therapy. Thus, our study identified a molecular interaction involved in tumor vascular dysfunction and revealed an approach to promote a favorable tumor microenvironment for therapeutic intervention.

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