Special Issue "The Tumor Microenvironment of High Grade Serous Ovarian Cancer"

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (1 June 2018)

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editors

Guest Editor
Prof. Dr. M. Sharon Stack

Department of Chemistry and Biochemistry, Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46617, USA
Website 1 | Website 2 | E-Mail
Interests: mechanisms of metastasis, cell adhesion, extracellular matrix, proteolysis
Guest Editor
Prof. Dr. Kenneth P Nephew

Department of Cellular and Integrative Physiology, Cell, Molecular and Cancer Biology Program, Medical Sciences, Indiana University School of Medicine, Bloomington, IN 46202, USA
Website 1 | Website 2 | E-Mail
Interests: Women’s Cancers and Translational Research, Cancer Epigenetics (DNA methylation, histone modifications and non-coding RNAs), Cancer Stem Cells, Nuclear receptors/steroid hormone action/hormone-associated cancers, Drug resistance (ovarian and breast cancers)
Guest Editor
Dr. Joanna E. Burdette

Department of Medicinal Chemistry and Pharmacognosy, University of Illinois, Chicago, IL, USA
Website | E-Mail
Interests: ovarian cancers, drug discovery, anti-cancer molecules
Guest Editor
Dr. Anirban K. Mitra

Medical Sciences Program, Indiana University School of Medicine, Bloomington, Indiana, USA
Website | E-Mail
Interests: ovarian cancer metastasis, ovarian cancer

Special Issue Information

Dear colleagues,

This Special Issue focuses on high grade serous ovarian cancer (HGSOC) and the contribution of the tumor microenviroment (TME) to the unique features of this most lethal of the gynecologic malignancies and one of the most lethal of the peritoneal cancers. For those women diagnosed with advanced stage HGSOC, less than 30% of patients currently survive more than five years after diagnosis, with little improvement in overall survival in the past 40 years. Early metastatic dissemination into the peritoneal cavity is major driving force contributing poor prognosis. As HGSOC metastases have a highly complex TME, there is an urgent need to better understand the TME in general, its distinct components in particular, and the role of the TME in the context of disease recurrence and development of chemoresistance.

HGSOC uses the TME to facilitate tumor growth and metastatic dissemination; thus, an integrated understanding of the TME components, including malignant cells, surrounding host stromal cells, and infiltrating (recruited) immune cells is essential. In addition to cellular contributors to the TME, the role of ascites fluid components including soluble factors such as cytokines, chemokines, and growth factors; cell-cell and cell-matrix adhesion molecules; extracellular matrix remodeling; and abnormal vascular and lymphatic networks also warrant consideration. Identification of regulatory interactions between malignant and non-malignant cells in the context of TME evolution, tumor recurrence and chemoresistance will also prove informative. Additional attention on the relationship between the molecular mechanisms of HGSOC progression—including genomic, epigenomic and transcriptomic changes and alterations of the immune cell landscape—may provide attractive new molecular targets for HGSOC therapy. We welcome submissions focused on the key cellular and molecular aspects of the HGSOC TME and their role in disease progression and clinical outcome.

Prof. Dr. M. Sharon Stack
Dr. Kenneth P Nephew
Dr. Joanna E. Burdette
Dr. Anirban K. Mitra
Guest Editors

Manuscript Submission Information

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Keywords

  • Ovarian Cancer
  • Tumor Microenvironment
  • Metastasis
  • Chemoresistance
  • Epigenetics
  • Genomics
  • Cancer Stem Cells
  • Obesity
  • Growth Factors
  • Cytokines
  • Extracellular matrix
  • Spheroid
  • Angiogenesis
  • Ascites
  • Animal models
  • Age

Published Papers (21 papers)

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Editorial

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Open AccessEditorial The Tumor Microenvironment of High Grade Serous Ovarian Cancer
Received: 24 December 2018 / Accepted: 25 December 2018 / Published: 26 December 2018
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Abstract
The Special Issue on high grade serous ovarian cancer (HGSOC) and the contribution of the tumor micro-environment (TME) consisted of reviews contributed by leaders in the ovarian cancer (OC) field. [...] Full article

Review

Jump to: Editorial

Open AccessReview Molecular Mechanisms Regulating Organ-Specific Metastases in Epithelial Ovarian Carcinoma
Cancers 2018, 10(11), 444; https://doi.org/10.3390/cancers10110444
Received: 13 September 2018 / Revised: 2 November 2018 / Accepted: 13 November 2018 / Published: 15 November 2018
Cited by 2 | PDF Full-text (871 KB) | HTML Full-text | XML Full-text
Abstract
Epithelial ovarian carcinoma is the most predominant type of ovarian carcinoma, the deadliest gynecologic malignancy. It is typically diagnosed late when the cancer has already metastasized. Transcoelomic metastasis is the most predominant mechanism of dissemination from epithelial ovarian carcinoma, although both hematogenously and [...] Read more.
Epithelial ovarian carcinoma is the most predominant type of ovarian carcinoma, the deadliest gynecologic malignancy. It is typically diagnosed late when the cancer has already metastasized. Transcoelomic metastasis is the most predominant mechanism of dissemination from epithelial ovarian carcinoma, although both hematogenously and lymphogenously spread metastases also occur. In this review, we describe molecular mechanisms known to regulate organ-specific metastasis from epithelial ovarian carcinoma. We begin by discussing the sites colonized by metastatic ovarian carcinoma and rank them in the order of prevalence. Next, we review the mechanisms regulating the transcoelomic metastasis. Within this chapter, we specifically focus on the mechanisms that were demonstrated to regulate peritoneal adhesion—one of the first steps in the transcoelomic metastatic cascade. Furthermore, we describe mechanisms of the transcoelomic metastasis known to regulate colonization of specific sites within the peritoneal cavity, including the omentum. Mechanisms underlying hematogenous and lymphogenous metastatic spread are less comprehensively studied in ovarian cancer, and we summarize mechanisms that were identified to date. Lastly, we discuss the outcomes of the clinical trials that attempted to target some of the mechanisms described in this review. Full article
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Open AccessReview Cell Origins of High-Grade Serous Ovarian Cancer
Cancers 2018, 10(11), 433; https://doi.org/10.3390/cancers10110433
Received: 22 October 2018 / Revised: 3 November 2018 / Accepted: 7 November 2018 / Published: 12 November 2018
Cited by 1 | PDF Full-text (564 KB) | HTML Full-text | XML Full-text
Abstract
High-grade serous ovarian cancer, also known as high-grade serous carcinoma (HGSC), is the most common and deadliest type of ovarian cancer. HGSC appears to arise from the ovary, fallopian tube, or peritoneum. As most HGSC cases present with widespread peritoneal metastases, it is [...] Read more.
High-grade serous ovarian cancer, also known as high-grade serous carcinoma (HGSC), is the most common and deadliest type of ovarian cancer. HGSC appears to arise from the ovary, fallopian tube, or peritoneum. As most HGSC cases present with widespread peritoneal metastases, it is often not clear where HGSC truly originates. Traditionally, the ovarian surface epithelium (OSE) was long believed to be the origin of HGSC. Since the late 1990s, the fallopian tube epithelium has emerged as a potential primary origin of HGSC. Particularly, serous tubal intraepithelial carcinoma (STIC), a noninvasive tumor lesion formed preferentially in the distal fallopian tube epithelium, was proposed as a precursor for HGSC. It was hypothesized that STIC lesions would progress, over time, to malignant and metastatic HGSC, arising from the fallopian tube or after implanting on the ovary or peritoneum. Many clinical studies and several mouse models support the fallopian tube STIC origin of HGSC. Current evidence indicates that STIC may serve as a precursor for HGSC in high-risk women carrying germline BRCA1 or 2 mutations. Yet not all STIC lesions appear to progress to clinical HGSCs, nor would all HGSCs arise from STIC lesions, even in high-risk women. Moreover, the clinical importance of STIC remains less clear in women in the general population, in which 85–90% of all HGSCs arise. Recently, increasing attention has been brought to the possibility that many potential precursor or premalignant lesions, though composed of microscopically—and genetically—cancerous cells, do not advance to malignant tumors or lethal malignancies. Hence, rigorous causal evidence would be crucial to establish that STIC is a bona fide premalignant lesion for metastatic HGSC. While not all STICs may transform into malignant tumors, these lesions are clearly associated with increased risk for HGSC. Identification of the molecular characteristics of STICs that predict their malignant potential and clinical behavior would bolster the clinical importance of STIC. Also, as STIC lesions alone cannot account for all HGSCs, other potential cellular origins of HGSC need to be investigated. The fallopian tube stroma in mice, for instance, has been shown to be capable of giving rise to metastatic HGSC, which faithfully recapitulates the clinical behavior and molecular aspect of human HGSC. Elucidating the precise cell(s) of origin of HGSC will be critical for improving the early detection and prevention of ovarian cancer, ultimately reducing ovarian cancer mortality. Full article
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Open AccessReview Cancer Associated Fibroblasts: Naughty Neighbors That Drive Ovarian Cancer Progression
Cancers 2018, 10(11), 406; https://doi.org/10.3390/cancers10110406
Received: 12 September 2018 / Revised: 19 October 2018 / Accepted: 24 October 2018 / Published: 29 October 2018
Cited by 2 | PDF Full-text (1087 KB) | HTML Full-text | XML Full-text
Abstract
Ovarian cancer is the most lethal gynecologic malignancy, and patient prognosis has not improved significantly over the last several decades. In order to improve therapeutic approaches and patient outcomes, there is a critical need for focused research towards better understanding of the disease. [...] Read more.
Ovarian cancer is the most lethal gynecologic malignancy, and patient prognosis has not improved significantly over the last several decades. In order to improve therapeutic approaches and patient outcomes, there is a critical need for focused research towards better understanding of the disease. Recent findings have revealed that the tumor microenvironment plays an essential role in promoting cancer progression and metastasis. The tumor microenvironment consists of cancer cells and several different types of normal cells recruited and reprogrammed by the cancer cells to produce factors beneficial to tumor growth and spread. These normal cells present within the tumor, along with the various extracellular matrix proteins and secreted factors, constitute the tumor stroma and can compose 10–60% of the tumor volume. Cancer associated fibroblasts (CAFs) are a major constituent of the tumor microenvironment, and play a critical role in promoting many aspects of tumor function. This review will describe the various hypotheses about the origin of CAFs, their major functions in the tumor microenvironment in ovarian cancer, and will discuss the potential of targeting CAFs as a possible therapeutic approach. Full article
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Open AccessReview Bipolar Tumor-Associated Macrophages in Ovarian Cancer as Targets for Therapy
Cancers 2018, 10(10), 366; https://doi.org/10.3390/cancers10100366
Received: 22 August 2018 / Revised: 22 September 2018 / Accepted: 23 September 2018 / Published: 29 September 2018
Cited by 2 | PDF Full-text (1055 KB) | HTML Full-text | XML Full-text
Abstract
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 [...] Read more.
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. Full article
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Open AccessReview Ovarian Tumor Microenvironment Signaling: Convergence on the Rac1 GTPase
Cancers 2018, 10(10), 358; https://doi.org/10.3390/cancers10100358
Received: 1 September 2018 / Revised: 25 September 2018 / Accepted: 25 September 2018 / Published: 27 September 2018
Cited by 1 | PDF Full-text (2431 KB) | HTML Full-text | XML Full-text
Abstract
The tumor microenvironment for epithelial ovarian cancer is complex and rich in bioactive molecules that modulate cell-cell interactions and stimulate numerous signal transduction cascades. These signals ultimately modulate all aspects of tumor behavior including progression, metastasis and therapeutic response. Many of the signaling [...] Read more.
The tumor microenvironment for epithelial ovarian cancer is complex and rich in bioactive molecules that modulate cell-cell interactions and stimulate numerous signal transduction cascades. These signals ultimately modulate all aspects of tumor behavior including progression, metastasis and therapeutic response. Many of the signaling pathways converge on the small GTPase Ras-related C3 botulinum toxin substrate (Rac)1. In addition to regulating actin cytoskeleton remodeling necessary for tumor cell adhesion, migration and invasion, Rac1 through its downstream effectors, regulates cancer cell survival, tumor angiogenesis, phenotypic plasticity, quiescence, and resistance to therapeutics. In this review we discuss evidence for Rac1 activation within the ovarian tumor microenvironment, mechanisms of Rac1 dysregulation as they apply to ovarian cancer, and the potential benefits of targeting aberrant Rac1 activity in this disease. The potential for Rac1 contribution to extraperitoneal dissemination of ovarian cancer is addressed. Full article
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Open AccessReview Oxidative Phosphorylation: A Target for Novel Therapeutic Strategies Against Ovarian Cancer
Cancers 2018, 10(9), 337; https://doi.org/10.3390/cancers10090337
Received: 25 July 2018 / Revised: 13 September 2018 / Accepted: 17 September 2018 / Published: 18 September 2018
Cited by 1 | PDF Full-text (1078 KB) | HTML Full-text | XML Full-text
Abstract
Aerobic glycolysis is an important metabolic adaptation of cancer cells. There is growing evidence that oxidative phosphorylation is also an active metabolic pathway in many tumors, including in high grade serous ovarian cancer. Metastasized ovarian tumors use fatty acids for their energy needs. [...] Read more.
Aerobic glycolysis is an important metabolic adaptation of cancer cells. There is growing evidence that oxidative phosphorylation is also an active metabolic pathway in many tumors, including in high grade serous ovarian cancer. Metastasized ovarian tumors use fatty acids for their energy needs. There is also evidence of ovarian cancer stem cells privileging oxidative phosphorylation (OXPHOS) for their metabolic needs. Metformin and thiazolidinediones such as rosiglitazone restrict tumor growth by inhibiting specific steps in the mitochondrial electron transport chain. These observations suggest that strategies to interfere with oxidative phosphorylation should be considered for the treatment of ovarian tumors. Here, we review the literature that supports this hypothesis and describe potential agents and critical control points in the oxidative phosphorylation pathway that can be targeted using small molecule agents. In this review, we also discuss potential barriers that can reduce the efficacy of the inhibitors of oxidative phosphorylation. Full article
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Open AccessReview Regulation of Ovarian Cancer Prognosis by Immune Cells in the Tumor Microenvironment
Cancers 2018, 10(9), 302; https://doi.org/10.3390/cancers10090302
Received: 8 August 2018 / Revised: 28 August 2018 / Accepted: 29 August 2018 / Published: 1 September 2018
Cited by 3 | PDF Full-text (887 KB) | HTML Full-text | XML Full-text
Abstract
It is estimated that in the United States in 2018 there will be 22,240 new cases of ovarian cancer and 14,070 deaths due to this malignancy. The most common subgroup of this disease is high-grade serous ovarian cancer (HGSOC), which is known for [...] Read more.
It is estimated that in the United States in 2018 there will be 22,240 new cases of ovarian cancer and 14,070 deaths due to this malignancy. The most common subgroup of this disease is high-grade serous ovarian cancer (HGSOC), which is known for its aggressiveness, high recurrence rate, metastasis to other sites, and the development of resistance to conventional therapy. It is important to understand the ovarian cancer tumor microenvironment (TME) from the viewpoint of the function of pre-existing immune cells, as immunocompetent cells are crucial to mounting robust antitumor responses to prevent visible tumor lesions, disease progression, or recurrence. Networks consisting of innate and adaptive immune cells, metabolic pathways, intracellular signaling molecules, and a vast array of soluble factors, shape the pathogenic nature of the TME and are useful prognostic indicators of responses to conventional therapy and immunotherapy, and subsequent survival rates. This review highlights key immune cells and soluble molecules in the TME of ovarian cancer, which are important in the development of effective antitumor immunity, as well as those that impair effector T cell activity. A more insightful knowledge of the HGSOC TME will reveal potential immune biomarkers to aid in the early detection of this disease, as well as biomarkers that may be targeted to advance the design of novel therapies that induce potent antitumor immunity and survival benefit. Full article
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Open AccessReview Heated Intraperitoneal Chemotherapy in the Management of Advanced Ovarian Cancer
Cancers 2018, 10(9), 296; https://doi.org/10.3390/cancers10090296
Received: 5 June 2018 / Revised: 14 August 2018 / Accepted: 16 August 2018 / Published: 1 September 2018
Cited by 1 | PDF Full-text (189 KB) | HTML Full-text | XML Full-text
Abstract
Heated intraperitoneal chemotherapy (HIPEC) has several potential benefits. Higher doses of chemotherapy can be used with HIPEC because the plasma-peritoneal barrier results in little absorption into the blood stream. HIPEC offers higher peritoneal penetration in comparison to an intravenous (IV) regimen and does [...] Read more.
Heated intraperitoneal chemotherapy (HIPEC) has several potential benefits. Higher doses of chemotherapy can be used with HIPEC because the plasma-peritoneal barrier results in little absorption into the blood stream. HIPEC offers higher peritoneal penetration in comparison to an intravenous (IV) regimen and does not have the traditional normothermic intraperitoneal (IP) regimen limitation of post-operative adhesions. Hyperthermia itself has cytotoxic effects and can potentiate antineoplastic effects of chemotherapy in part by increasing the depth of tumor penetration by up to 3 mm. For the treatment of ovarian cancer, HIPEC has been evaluated in the recurrent setting with secondary cytoreduction. Recent studies, including a prospective trial, have evaluated its role in primary management of ovarian cancer. This review summarizes previous and ongoing studies regarding the use of HIPEC in the management of ovarian cancer. Full article
Open AccessReview Epigenetic Crosstalk between the Tumor Microenvironment and Ovarian Cancer Cells: A Therapeutic Road Less Traveled
Cancers 2018, 10(9), 295; https://doi.org/10.3390/cancers10090295
Received: 22 July 2018 / Revised: 27 August 2018 / Accepted: 28 August 2018 / Published: 30 August 2018
Cited by 1 | PDF Full-text (1055 KB) | HTML Full-text | XML Full-text
Abstract
Metastatic dissemination of epithelial ovarian cancer (EOC) predominantly occurs through direct cell shedding from the primary tumor into the intra-abdominal cavity that is filled with malignant ascitic effusions. Facilitated by the fluid flow, cells distribute throughout the cavity, broadly seed and invade through [...] Read more.
Metastatic dissemination of epithelial ovarian cancer (EOC) predominantly occurs through direct cell shedding from the primary tumor into the intra-abdominal cavity that is filled with malignant ascitic effusions. Facilitated by the fluid flow, cells distribute throughout the cavity, broadly seed and invade through peritoneal lining, and resume secondary tumor growth in abdominal and pelvic organs. At all steps of this unique metastatic process, cancer cells exist within a multidimensional tumor microenvironment consisting of intraperitoneally residing cancer-reprogramed fibroblasts, adipose, immune, mesenchymal stem, mesothelial, and vascular cells that exert miscellaneous bioactive molecules into malignant ascites and contribute to EOC progression and metastasis via distinct molecular mechanisms and epigenetic dysregulation. This review outlines basic epigenetic mechanisms, including DNA methylation, histone modifications, chromatin remodeling, and non-coding RNA regulators, and summarizes current knowledge on reciprocal interactions between each participant of the EOC cellular milieu and tumor cells in the context of aberrant epigenetic crosstalk. Promising research directions and potential therapeutic strategies that may encompass epigenetic tailoring as a component of complex EOC treatment are discussed. Full article
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Open AccessReview The Impact of Mesothelin in the Ovarian Cancer Tumor Microenvironment
Cancers 2018, 10(9), 277; https://doi.org/10.3390/cancers10090277
Received: 8 June 2018 / Revised: 17 August 2018 / Accepted: 18 August 2018 / Published: 21 August 2018
Cited by 2 | PDF Full-text (1031 KB) | HTML Full-text | XML Full-text
Abstract
Ovarian cancer is the deadliest gynecological disease among U.S. women. Poor 5-year survival rates (<30%) are due to presentation of most women at diagnosis with advanced stage disease with widely disseminated intraperitoneal metastasis. However, when diagnosed before metastatic propagation the overall 5-year survival [...] Read more.
Ovarian cancer is the deadliest gynecological disease among U.S. women. Poor 5-year survival rates (<30%) are due to presentation of most women at diagnosis with advanced stage disease with widely disseminated intraperitoneal metastasis. However, when diagnosed before metastatic propagation the overall 5-year survival rate is >90%. Metastasizing tumor cells grow rapidly and aggressively attach to the mesothelium of all organs within the peritoneal cavity, including the parietal peritoneum and the omentum, producing secondary lesions. In this review, the involvement of mesothelin (MSLN) in the tumor microenvironment is discussed. MSLN, a 40kDa glycoprotein that is overexpressed in many cancers including ovarian and mesotheliomas is suggested to play a role in cell survival, proliferation, tumor progression, and adherence. However, the biological function of MSLN is not fully understood as MSLN knockout mice do not present with an abnormal phenotype. Conversely, MSLN has been shown to bind to the ovarian cancer antigen, CA-125, and thought to play a role in the peritoneal diffusion of ovarian tumor cells. Although the cancer-specific expression of MSLN makes it a potential therapeutic target, more studies are needed to validate the role of MSLN in tumor metastasis. Full article
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Open AccessReview Targeting the Microenvironment in High Grade Serous Ovarian Cancer
Cancers 2018, 10(8), 266; https://doi.org/10.3390/cancers10080266
Received: 20 July 2018 / Revised: 3 August 2018 / Accepted: 6 August 2018 / Published: 10 August 2018
Cited by 3 | PDF Full-text (2399 KB) | HTML Full-text | XML Full-text
Abstract
Cancer–stroma interactions play a key role in cancer progression and response to standard chemotherapy. Here, we provide a summary of the mechanisms by which the major cellular components of the ovarian cancer (OC) tumor microenvironment (TME) including cancer-associated fibroblasts (CAFs), myeloid, immune, endothelial, [...] Read more.
Cancer–stroma interactions play a key role in cancer progression and response to standard chemotherapy. Here, we provide a summary of the mechanisms by which the major cellular components of the ovarian cancer (OC) tumor microenvironment (TME) including cancer-associated fibroblasts (CAFs), myeloid, immune, endothelial, and mesothelial cells potentiate cancer progression. High-grade serous ovarian cancer (HGSOC) is characterized by a pro-inflammatory and angiogenic signature. This profile is correlated with clinical outcomes and can be a target for therapy. Accumulation of malignant ascites in the peritoneal cavity allows for secreted factors to fuel paracrine and autocrine circuits that augment cancer cell proliferation and invasiveness. Adhesion of cancer cells to the mesothelial matrix promotes peritoneal tumor dissemination and represents another attractive target to prevent metastasis. The immunosuppressed tumor milieu of HGSOC is permissive for tumor growth and can be modulated therapeutically. Results of emerging preclinical and clinical trials testing TME-modulating therapeutics for the treatment of OC are highlighted. Full article
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Open AccessReview Organotypic 3D Models of the Ovarian Cancer Tumor Microenvironment
Cancers 2018, 10(8), 265; https://doi.org/10.3390/cancers10080265
Received: 19 June 2018 / Revised: 3 August 2018 / Accepted: 8 August 2018 / Published: 9 August 2018
Cited by 3 | PDF Full-text (4783 KB) | HTML Full-text | XML Full-text
Abstract
Ovarian cancer progression involves multifaceted and variable tumor microenvironments (TMEs), from the in situ carcinoma in the fallopian tube or ovary to dissemination into the peritoneal cavity as single cells or spheroids and attachment to the mesothelial-lined surfaces of the omentum, bowel, and [...] Read more.
Ovarian cancer progression involves multifaceted and variable tumor microenvironments (TMEs), from the in situ carcinoma in the fallopian tube or ovary to dissemination into the peritoneal cavity as single cells or spheroids and attachment to the mesothelial-lined surfaces of the omentum, bowel, and abdominal wall. The TME comprises the tumor vasculature and lymphatics (including endothelial cells and pericytes), in addition to mesothelial cells, fibroblasts, immune cells, adipocytes and extracellular matrix (ECM) proteins. When generating 3D models of the ovarian cancer TME, researchers must incorporate the most relevant stromal components depending on the TME in question (e.g., early or late disease). Such complexity cannot be captured by monolayer 2D culture systems. Moreover, immortalized stromal cell lines, such as mesothelial or fibroblast cell lines, do not always behave the same as primary cells whose response in functional assays may vary from donor to donor; 3D models with primary stromal cells may have more physiological relevance than those using stromal cell lines. In the current review, we discuss the latest developments in organotypic 3D models of the ovarian cancer early metastatic microenvironment. Organotypic culture models comprise two or more interacting cell types from a particular tissue. We focus on organotypic 3D models that include at least one type of primary stromal cell type in an ECM background, such as collagen or fibronectin, plus ovarian cancer cells. We provide an overview of the two most comprehensive current models—a 3D model of the omental mesothelium and a microfluidic model. We describe the cellular and non-cellular components of the models, the incorporation of mechanical forces, and how the models have been adapted and utilized in functional assays. Finally, we review a number of 3D models that do not incorporate primary stromal cells and summarize how integration of current models may be the next essential step in tackling the complexity of the different ovarian cancer TMEs. Full article
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Open AccessReview UnPAXing the Divergent Roles of PAX2 and PAX8 in High-Grade Serous Ovarian Cancer
Cancers 2018, 10(8), 262; https://doi.org/10.3390/cancers10080262
Received: 14 June 2018 / Revised: 1 August 2018 / Accepted: 4 August 2018 / Published: 8 August 2018
Cited by 2 | PDF Full-text (376 KB) | HTML Full-text | XML Full-text
Abstract
High-grade serous ovarian cancer is a deadly disease that can originate from the fallopian tube or the ovarian surface epithelium. The PAX (paired box) genes PAX2 and PAX8 are lineage-specific transcription factors required during development of the fallopian tube but not in the [...] Read more.
High-grade serous ovarian cancer is a deadly disease that can originate from the fallopian tube or the ovarian surface epithelium. The PAX (paired box) genes PAX2 and PAX8 are lineage-specific transcription factors required during development of the fallopian tube but not in the development of the ovary. PAX2 expression is lost early in serous cancer progression, while PAX8 is expressed ubiquitously. These proteins are implicated in migration, invasion, proliferation, cell survival, stem cell maintenance, and tumor growth. Hence, targeting PAX2 and PAX8 represents a promising drug strategy that could inhibit these pro-tumorigenic effects. In this review, we examine the implications of PAX2 and PAX8 expression in the cell of origin of serous cancer and their potential efficacy as drug targets by summarizing their role in the molecular pathogenesis of ovarian cancer. Full article
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Open AccessReview The Endometriotic Tumor Microenvironment in Ovarian Cancer
Cancers 2018, 10(8), 261; https://doi.org/10.3390/cancers10080261
Received: 29 June 2018 / Revised: 31 July 2018 / Accepted: 2 August 2018 / Published: 7 August 2018
Cited by 4 | PDF Full-text (872 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Women with endometriosis are at increased risk of developing ovarian cancer, specifically ovarian endometrioid, low-grade serous, and clear-cell adenocarcinoma. An important clinical caveat to the association of endometriosis with ovarian cancer is the improved prognosis for women with endometriosis at time of ovarian [...] Read more.
Women with endometriosis are at increased risk of developing ovarian cancer, specifically ovarian endometrioid, low-grade serous, and clear-cell adenocarcinoma. An important clinical caveat to the association of endometriosis with ovarian cancer is the improved prognosis for women with endometriosis at time of ovarian cancer staging. Whether endometriosis-associated ovarian cancers develop from the molecular transformation of endometriosis or develop because of the endometriotic tumor microenvironment remain unknown. Additionally, how the presence of endometriosis improves prognosis is also undefined, but likely relies on the endometriotic microenvironment. The unique tumor microenvironment of endometriosis is composed of epithelial, stromal, and immune cells, which adapt to survive in hypoxic conditions with high levels of iron, estrogen, and inflammatory cytokines and chemokines. Understanding the unique molecular features of the endometriotic tumor microenvironment may lead to impactful precision therapies and/or modalities for prevention. A challenge to this important study is the rarity of well-characterized clinical samples and the limited model systems. In this review, we will describe the unique molecular features of endometriosis-associated ovarian cancers, the endometriotic tumor microenvironment, and available model systems for endometriosis-associated ovarian cancers. Continued research on these unique ovarian cancers may lead to improved prevention and treatment options. Full article
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Open AccessReview The Role of Inflammation and Inflammatory Mediators in the Development, Progression, Metastasis, and Chemoresistance of Epithelial Ovarian Cancer
Cancers 2018, 10(8), 251; https://doi.org/10.3390/cancers10080251
Received: 14 June 2018 / Revised: 20 July 2018 / Accepted: 24 July 2018 / Published: 30 July 2018
Cited by 3 | PDF Full-text (1378 KB) | HTML Full-text | XML Full-text
Abstract
Inflammation plays a role in the initiation and development of many types of cancers, including epithelial ovarian cancer (EOC) and high grade serous ovarian cancer (HGSC), a type of EOC. There are connections between EOC and both peritoneal and ovulation-induced inflammation. Additionally, EOCs [...] Read more.
Inflammation plays a role in the initiation and development of many types of cancers, including epithelial ovarian cancer (EOC) and high grade serous ovarian cancer (HGSC), a type of EOC. There are connections between EOC and both peritoneal and ovulation-induced inflammation. Additionally, EOCs have an inflammatory component that contributes to their progression. At sites of inflammation, epithelial cells are exposed to increased levels of inflammatory mediators such as reactive oxygen species, cytokines, prostaglandins, and growth factors that contribute to increased cell division, and genetic and epigenetic changes. These exposure-induced changes promote excessive cell proliferation, increased survival, malignant transformation, and cancer development. Furthermore, the pro-inflammatory tumor microenvironment environment (TME) contributes to EOC metastasis and chemoresistance. In this review we will discuss the roles inflammation and inflammatory mediators play in the development, progression, metastasis, and chemoresistance of EOC. Full article
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Open AccessFeature PaperReview Ovarian Cancer Immunotherapy: Preclinical Models and Emerging Therapeutics
Cancers 2018, 10(8), 244; https://doi.org/10.3390/cancers10080244
Received: 29 June 2018 / Revised: 20 July 2018 / Accepted: 23 July 2018 / Published: 26 July 2018
Cited by 5 | PDF Full-text (578 KB) | HTML Full-text | XML Full-text
Abstract
Immunotherapy has emerged as one of the most promising approaches for ovarian cancer treatment. The tumor microenvironment (TME) is a key factor to consider when stimulating antitumoral responses as it consists largely of tumor promoting immunosuppressive cell types that attenuate antitumor immunity. As [...] Read more.
Immunotherapy has emerged as one of the most promising approaches for ovarian cancer treatment. The tumor microenvironment (TME) is a key factor to consider when stimulating antitumoral responses as it consists largely of tumor promoting immunosuppressive cell types that attenuate antitumor immunity. As our understanding of the determinants of the TME composition grows, we have begun to appreciate the need to address both inter- and intra-tumor heterogeneity, mutation/neoantigen burden, immune landscape, and stromal cell contributions. The majority of immunotherapy studies in ovarian cancer have been performed using the well-characterized murine ID8 ovarian carcinoma model. Numerous other animal models of ovarian cancer exist, but have been underutilized because of their narrow initial characterizations in this context. Here, we describe animal models that may be untapped resources for the immunotherapy field because of their shared genomic alterations and histopathology with human ovarian cancer. We also shed light on the strengths and limitations of these models, and the knowledge gaps that need to be addressed to enhance the utility of preclinical models for testing novel immunotherapeutic approaches. Full article
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Open AccessFeature PaperReview The Tumor Microenvironment of Epithelial Ovarian Cancer and Its Influence on Response to Immunotherapy
Cancers 2018, 10(8), 242; https://doi.org/10.3390/cancers10080242
Received: 23 June 2018 / Revised: 16 July 2018 / Accepted: 20 July 2018 / Published: 24 July 2018
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Abstract
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 [...] Read more.
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. Full article
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Open AccessFeature PaperReview Can Stemness and Chemoresistance Be Therapeutically Targeted via Signaling Pathways in Ovarian Cancer?
Cancers 2018, 10(8), 241; https://doi.org/10.3390/cancers10080241
Received: 15 June 2018 / Revised: 12 July 2018 / Accepted: 17 July 2018 / Published: 24 July 2018
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Abstract
Ovarian cancer is the most lethal gynecological malignancy. Poor overall survival, particularly for patients with high grade serous (HGS) ovarian cancer, is often attributed to late stage at diagnosis and relapse following chemotherapy. HGS ovarian cancer is a heterogenous disease in that few [...] Read more.
Ovarian cancer is the most lethal gynecological malignancy. Poor overall survival, particularly for patients with high grade serous (HGS) ovarian cancer, is often attributed to late stage at diagnosis and relapse following chemotherapy. HGS ovarian cancer is a heterogenous disease in that few genes are consistently mutated between patients. Additionally, HGS ovarian cancer is characterized by high genomic instability. For these reasons, personalized approaches may be necessary for effective treatment and cure. Understanding the molecular mechanisms that contribute to tumor metastasis and chemoresistance are essential to improve survival rates. One favored model for tumor metastasis and chemoresistance is the cancer stem cell (CSC) model. CSCs are cells with enhanced self-renewal properties that are enriched following chemotherapy. Elimination of this cell population is thought to be a mechanism to increase therapeutic response. Therefore, accurate identification of stem cell populations that are most clinically relevant is necessary. While many CSC identifiers (ALDH, OCT4, CD133, and side population) have been established, it is still not clear which population(s) will be most beneficial to target in patients. Therefore, there is a critical need to characterize CSCs with reliable markers and find their weaknesses that will make the CSCs amenable to therapy. Many signaling pathways are implicated for their roles in CSC initiation and maintenance. Therapeutically targeting pathways needed for CSC initiation or maintenance may be an effective way of treating HGS ovarian cancer patients. In conclusion, the prognosis for HGS ovarian cancer may be improved by combining CSC phenotyping with targeted therapies for pathways involved in CSC maintenance. Full article
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Open AccessReview With Great Age Comes Great Metastatic Ability: Ovarian Cancer and the Appeal of the Aging Peritoneal Microenvironment
Cancers 2018, 10(7), 230; https://doi.org/10.3390/cancers10070230
Received: 8 June 2018 / Revised: 2 July 2018 / Accepted: 4 July 2018 / Published: 10 July 2018
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Abstract
Age is one of the biggest risk factors for ovarian cancer. Older women have higher rates of diagnosis and death associated with the disease. In mouse models, it was shown that aged mice had greater tumor burden than their younger counterparts when intraperitoneally [...] Read more.
Age is one of the biggest risk factors for ovarian cancer. Older women have higher rates of diagnosis and death associated with the disease. In mouse models, it was shown that aged mice had greater tumor burden than their younger counterparts when intraperitoneally injected with ovarian tumor cells. While very few papers have been published looking at the direct link between ovarian cancer metastasis and age, there is a wealth of information on how age affects metastatic microenvironments. Mesothelial cells, the peritoneal extracellular matrix (ECM), fibroblasts, adipocytes and immune cells all exhibit distinct changes with age. The aged peritoneum hosts a higher number of senescent cells than its younger counterpart, in both the mesothelium and the stroma. These senescent cells promote an inflammatory profile and overexpress Matrix Metalloproteinases (MMPs), which remodel the ECM. The aged ECM is also modified by dysregulated collagen and laminin synthesis, increases in age-related crosslinking and increasing ovarian cancer invasion into the matrix. These changes contribute to a vastly different microenvironment in young and aged models for circulating ovarian cancer cells, creating a more welcoming “soil”. Full article
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Open AccessReview Lysophospholipid Signaling in the Epithelial Ovarian Cancer Tumor Microenvironment
Cancers 2018, 10(7), 227; https://doi.org/10.3390/cancers10070227
Received: 4 June 2018 / Revised: 3 July 2018 / Accepted: 5 July 2018 / Published: 9 July 2018
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Abstract
As one of the important cancer hallmarks, metabolism reprogramming, including lipid metabolism alterations, occurs in tumor cells and the tumor microenvironment (TME). It plays an important role in tumorigenesis, progression, and metastasis. Lipids, and several lysophospholipids in particular, are elevated in the blood, [...] Read more.
As one of the important cancer hallmarks, metabolism reprogramming, including lipid metabolism alterations, occurs in tumor cells and the tumor microenvironment (TME). It plays an important role in tumorigenesis, progression, and metastasis. Lipids, and several lysophospholipids in particular, are elevated in the blood, ascites, and/or epithelial ovarian cancer (EOC) tissues, making them not only useful biomarkers, but also potential therapeutic targets. While the roles and signaling of these lipids in tumor cells are extensively studied, there is a significant gap in our understanding of their regulations and functions in the context of the microenvironment. This review focuses on the recent study development in several oncolipids, including lysophosphatidic acid and sphingosine-1-phosphate, with emphasis on TME in ovarian cancer. Full article
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