Research

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15 pages, 3082 KiB

Open AccessArticle

Imaging Collagen Alterations in STICs and High Grade Ovarian Cancers in the Fallopian Tubes by Second Harmonic Generation Microscopy

by Eric C. Rentchler, Kristal L. Gant, Ronny Drapkin, Manish Patankar and Paul J. Campagnola

Cancers 2019, 11(11), 1805; https://doi.org/10.3390/cancers11111805 - 16 Nov 2019

Cited by 18 | Viewed by 3668

Abstract

The majority of high-grade serous ovarian cancers originate in the fallopian tubes, however, the corresponding structural changes in the extracellular matrix (ECM) have not been well-characterized. This information could provide new insight into the carcinogenesis and provide the basis for new diagnostic tools. [...] Read more.

The majority of high-grade serous ovarian cancers originate in the fallopian tubes, however, the corresponding structural changes in the extracellular matrix (ECM) have not been well-characterized. This information could provide new insight into the carcinogenesis and provide the basis for new diagnostic tools. We have previously used the collagen-specific Second Harmonic Generation (SHG) microscopy to probe collagen fiber alterations in high-grade serous ovarian cancer and in other ovarian tumors, and showed they could be uniquely identified by machine learning approaches. Here we couple SHG imaging of serous tubal intra-epithelial carcinomas (STICs), high-grade cancers, and normal regions of the fallopian tubes, using three distinct image analysis approaches to form a classification scheme based on the respective collagen fiber morphology. Using a linear discriminant analysis, we achieved near 100% classification accuracy between high-grade disease and the other tissues, where the STICs and normal regions were differentiated with ~75% accuracy. Importantly, the collagen in high-grade disease in both the fallopian tube and the ovary itself have a similar collagen morphology, further substantiating the metastasis between these sites. This analysis provides a new method of classification, but also quantifies the structural changes in the disease, which may provide new insight into metastasis. Full article

(This article belongs to the Special Issue Ovarian Cancer Metastasis)

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22 pages, 3154 KiB

Open AccessArticle

Transcriptome Profiling Reveals Matrisome Alteration as a Key Feature of Ovarian Cancer Progression

by Sumegha Mitra, Kartikeya Tiwari, Ram Podicheti, Taruni Pandhiri, Douglas B. Rusch, Andrea Bonetto, Chi Zhang and Anirban K. Mitra

Cancers 2019, 11(10), 1513; https://doi.org/10.3390/cancers11101513 - 09 Oct 2019

Cited by 22 | Viewed by 5113

Abstract

Background: Ovarian cancer is the most lethal gynecologic malignancy. There is a lack of comprehensive investigation of disease initiation and progression, including gene expression changes during early metastatic colonization. Methods: RNA-sequencing (RNA-seq) was done with matched primary tumors and fallopian tubes (n = [...] Read more.

Background: Ovarian cancer is the most lethal gynecologic malignancy. There is a lack of comprehensive investigation of disease initiation and progression, including gene expression changes during early metastatic colonization. Methods: RNA-sequencing (RNA-seq) was done with matched primary tumors and fallopian tubes (n = 8 pairs) as well as matched metastatic and primary tumors (n = 11 pairs) from ovarian cancer patients. Since these are end point analyses, it was combined with RNA-seq using high-grade serous ovarian cancer cells seeded on an organotypic three-dimensional (3D) culture model of the omentum, mimicking early metastasis. This comprehensive approach revealed key changes in gene expression occurring in ovarian cancer initiation and metastasis, including early metastatic colonization. Results: 2987 genes were significantly deregulated in primary tumors compared to fallopian tubes, 845 genes were differentially expressed in metastasis compared to primary tumors and 304 genes were common to both. An assessment of patient metastasis and 3D omental culture model of early metastatic colonization revealed 144 common genes that were altered during early colonization and remain deregulated even in the fully developed metastasis. Deregulation of the matrisome was a key process in early and late metastasis. Conclusion: These findings will help in understanding the key pathways involved in ovarian cancer progression and eventually targeting those pathways for therapeutic interventions. Full article

(This article belongs to the Special Issue Ovarian Cancer Metastasis)

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17 pages, 4817 KiB

Open AccessArticle

Keratin-14 (KRT14) Positive Leader Cells Mediate Mesothelial Clearance and Invasion by Ovarian Cancer Cells

by Maree Bilandzic, Adam Rainczuk, Emma Green, Nicole Fairweather, Thomas W. Jobling, Magdalena Plebanski and Andrew N. Stephens

Cancers 2019, 11(9), 1228; https://doi.org/10.3390/cancers11091228 - 22 Aug 2019

Cited by 34 | Viewed by 5573

Abstract

Epithelial ovarian cancer metastasis is driven by spheroids, which are heterogeneous cancer cell aggregates released from the primary tumour mass that passively disseminate throughout the peritoneal cavity to promote tumour spread, disease recurrence, and acquired chemoresistance. Despite their clinical importance, the molecular events [...] Read more.

Epithelial ovarian cancer metastasis is driven by spheroids, which are heterogeneous cancer cell aggregates released from the primary tumour mass that passively disseminate throughout the peritoneal cavity to promote tumour spread, disease recurrence, and acquired chemoresistance. Despite their clinical importance, the molecular events that control spheroid attachment and invasion into underlying healthy tissues remain poorly understood. We examined a novel in vitro invasion model using imaging mass spectrometry to establish a “snapshot” of the spheroid/mesothelial interface. Amongst numerous adhesion-related proteins, we identified a sub-population of highly motile, invasive cells that expressed the basal epithelial marker KRT14 as an absolute determinant of invasive potential. The loss of KRT14 completely abrogated the invasive capacity, but had no impact on cell viability or proliferation, suggesting an invasion-specific role. Our data demonstrate KRT14 cells as an ovarian cancer “leader cell” phenotype underlying tumor invasion, and suggest their importance as a clinically relevant target in directed anti-tumour therapies. Full article

(This article belongs to the Special Issue Ovarian Cancer Metastasis)

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13 pages, 3107 KiB

Open AccessArticle

Extracapsular Lymph Node Involvement in Ovarian Carcinoma

by Sabine Heublein, Heiko Schulz, Frederik Marmé, Martin Angele, Bastian Czogalla, Alexander Burges, Sven Mahner, Doris Mayr, Udo Jeschke and Elisa Schmoeckel

Cancers 2019, 11(7), 924; https://doi.org/10.3390/cancers11070924 - 01 Jul 2019

Cited by 4 | Viewed by 4336

Abstract

Ovarian cancer (OC) spread to retro-peritoneal lymph nodes is detected in about one out of two patients at primary diagnosis. Whether the histologic pattern of lymph node involvement i.e., intra-(ICG) or extracapsular (ECG) cancer growth may affect patients’ prognosis remains unknown. The aim [...] Read more.

Ovarian cancer (OC) spread to retro-peritoneal lymph nodes is detected in about one out of two patients at primary diagnosis. Whether the histologic pattern of lymph node involvement i.e., intra-(ICG) or extracapsular (ECG) cancer growth may affect patients’ prognosis remains unknown. The aim of the current study was to analyze the prevalence of ECG and ICG in lymph node positive ovarian cancer. We further investigated whether ECG may be related to patients’ prognosis and whether biomarkers expressed in the primary tumor may predict the pattern of lymph node involvement. Lymph node samples stemming from 143 OC patients were examined for presence of ECG. Capsular extravasation was tested for statistical association with clinico-pathological variables. We further tested 27 biomarkers that had been determined in primary tumor tissue for their potential to predict ECG in metastatic lymph nodes. ECG was detected in 35 (24.5%) of 143 lymph node positive patients. High grade (p = 0.043), histologic subtype (p = 0.006) and high lymph node ratio (LNR) (p < 0.001) were positively correlated with presence of ECG. Both ECG (p = 0.024) and high LNR (p = 0.008) were predictive for shortened overall survival. A four-protein signature determined from the primary tumor tissue was associated with presence of concomitant extracapsular spread in lymph nodes of the respective patient. This work found extracapsular spread of lymph node metastasis to be a common feature of lymph node positive ovarian cancer. Since ECG was positively associated with grade, LNR and shortened overall survival, we hypothesize that the presence of ECG may be interpreted as an indicator of tumor aggressiveness. Full article

(This article belongs to the Special Issue Ovarian Cancer Metastasis)

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17 pages, 8426 KiB

Open AccessArticle

Loss of PTEN in Fallopian Tube Epithelium Results in Multicellular Tumor Spheroid Formation and Metastasis to the Ovary

by Matthew Dean, Vivian Jin, Tova M. Bergsten, Julia R. Austin, Daniel D. Lantvit, Angela Russo and Joanna E. Burdette

Cancers 2019, 11(6), 884; https://doi.org/10.3390/cancers11060884 - 25 Jun 2019

Cited by 23 | Viewed by 4592

Abstract

High-grade serous ovarian cancer (HGSOC) can originate in the fallopian tube and then spread to the ovary. Our objective was to evaluate the role of multicellular tumor spheroids (MTS) in ovarian metastasis. By testing a panel of murine oviductal epithelial (MOE) cells with [...] Read more.

High-grade serous ovarian cancer (HGSOC) can originate in the fallopian tube and then spread to the ovary. Our objective was to evaluate the role of multicellular tumor spheroids (MTS) in ovarian metastasis. By testing a panel of murine oviductal epithelial (MOE) cells with genetic alterations mimicking those seen in HGSOC, we found that loss of PTEN allowed MTS formation under ultra-low adhesion conditions. Confirming these results in vivo, MTS-like structures were observed in the oviducts of PAX8^Cre/+ PTEN^flox/flox mice. MOE PTEN^shRNA cells could incorporate up to 25% wild type cells into MTS, while higher percentages of wild type cells resulted in a loss of MTS formation. MTS formation allowed MOE PTEN^shRNA cells to survive better under ultra-low adhesion conditions than control cells. MTS also attached to the ovarian stroma, as would be exposed during ovulation. Interestingly, MTS more robustly cleared monolayers of murine ovarian surface epithelia than murine ovarian fibroblasts. When xenografted into the ovarian bursa, OVCAR8 MTS were able to form tumors in the ovary at a similar rate as an equal number of OVCAR8 cells grown on traditional cell culture plastic. In conclusion, loss of a single gene (PTEN) allows the fallopian tube epithelia to form MTS, which survive better under ultra-low adhesion conditions, attach to the extracellular matrix exposed during ovulation, and colonize the ovary. These results suggest that MTS may contribute to seeding of the ovary in HGSOC patients. Full article

(This article belongs to the Special Issue Ovarian Cancer Metastasis)

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24 pages, 7926 KiB

Open AccessArticle

Paclitaxel-Induced Src Activation Is Inhibited by Dasatinib Treatment, Independently of Cancer Stem Cell Properties, in a Mouse Model of Ovarian Cancer

by Elif Kadife, Emily Chan, Rodney Luwor, George Kannourakis, Jock Findlay and Nuzhat Ahmed

Cancers 2019, 11(2), 243; https://doi.org/10.3390/cancers11020243 - 19 Feb 2019

Cited by 11 | Viewed by 4139

Abstract

Approximately seventy percent of ovarian cancer patients succumb to the disease within the first 5 years of diagnosis, even after successful surgery and effective chemotherapy treatment. A small subset of chemotherapy resistant cancer stem cells (CSCs) cause relapse of ovarian cancers. This study [...] Read more.

Approximately seventy percent of ovarian cancer patients succumb to the disease within the first 5 years of diagnosis, even after successful surgery and effective chemotherapy treatment. A small subset of chemotherapy resistant cancer stem cells (CSCs) cause relapse of ovarian cancers. This study investigated the association between paclitaxel-mediated Src activation (p-Src) and CSC populations in driving ovarian cancer progression. We demonstrate that patients with high-stage serous ovarian carcinomas have significantly elevated levels of p-Src, compared to patient with low-stage and benign ovarian tumours. Additionally, p-Src was significantly enhanced in ascites-derived tumour cells obtained from recurrent patients, compared to chemonaïve patients. Paclitaxel treatment increased Src activation in ovarian cancer cells, causing enrichment of CSC marker expression in the surviving cells in vitro and in xenografts of nude mice. Dasatinib in combination with paclitaxel significantly suppressed p-Src in ovarian cancer cell lines and xenografts but had no effect on the expression of CSC markers. However, combination of paclitaxel and Dasatinib showed lower trend in invasion in liver and pancreas, compared to paclitaxel-only treatment. The tumours treated with combination therapy also had significantly lower infiltration of mononuclear cells. Robust recurrent tumour growth was observed in all mice groups after termination of treatments. The above results suggest that Dasatinib-mediated inhibition of p-Src may not be crucial for paclitaxel-induced CSC-mediated recurrence in ovarian cancer. Full article

(This article belongs to the Special Issue Ovarian Cancer Metastasis)

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Review

Jump to: Research

17 pages, 588 KiB

Open AccessReview

Productive Cross-Talk with the Microenvironment: A Critical Step in Ovarian Cancer Metastasis

by Mohamed A. Abd El Aziz, Komal Agarwal, Subramanyam Dasari and Anirban K. Mitra

Cancers 2019, 11(10), 1608; https://doi.org/10.3390/cancers11101608 - 21 Oct 2019

Cited by 24 | Viewed by 4486

Abstract

Most ovarian cancer patients present with disseminated disease at the time of their diagnosis, which is one of the main reasons for their poor prognosis. Metastasis is a multi-step process and a clear understanding of the mechanism of regulation of these steps remains [...] Read more.

Most ovarian cancer patients present with disseminated disease at the time of their diagnosis, which is one of the main reasons for their poor prognosis. Metastasis is a multi-step process and a clear understanding of the mechanism of regulation of these steps remains elusive. Productive reciprocal interactions between the metastasizing ovarian cancer cells and the microenvironment of the metastatic site or the tumor microenvironment play an important role in the successful establishment of metastasis. Much progress has been made in the recent past in our understanding of such interactions and the role of the cellular and acellular components of the microenvironment in establishing the metastatic tumors. This review will outline the role of the microenvironmental components of the ovarian cancer metastatic niche and their role in helping establish the metastatic tumors. Special emphasis will be given to the mesothelial cells, which are the first cells encountered by the cancer cells at the site of metastasis. Full article

(This article belongs to the Special Issue Ovarian Cancer Metastasis)

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16 pages, 1143 KiB

Open AccessReview

Cutaneous Metastases in Ovarian Cancer

by Isao Otsuka

Cancers 2019, 11(9), 1292; https://doi.org/10.3390/cancers11091292 - 02 Sep 2019

Cited by 16 | Viewed by 4208

Abstract

Skin metastases in ovarian cancer are uncommon, but their incidence may be increasing due to improved survival rates. Skin metastases can be divided into umbilical metastases, which are known as Sister Joseph nodules (SJNs) and are associated with peritoneal metastasis, and non-SJN skin [...] Read more.

Skin metastases in ovarian cancer are uncommon, but their incidence may be increasing due to improved survival rates. Skin metastases can be divided into umbilical metastases, which are known as Sister Joseph nodules (SJNs) and are associated with peritoneal metastasis, and non-SJN skin metastases, which usually develop within surgical scars and in the vicinity of superficial lymphadenopathy. As most skin metastases develop after specific conditions, recognition of preceding metastatic diseases and prior treatments is necessary for early diagnosis of skin lesions. The prognosis of skin metastases in ovarian cancer varies widely since they are heterogeneous in the site of lesion and the time of appearance. Patients with SJNs at initial diagnosis and patients with surgical scar recurrences without concomitant metastases may have prolonged survival with a combination of surgery and chemotherapy. In patients who developed skin recurrences as a late manifestation, symptoms should be treated with external beam radiotherapy and immune response modifiers. Immune checkpoint blockade can enhance anti-tumor immunity and induce durable clinical responses in multiple tumor types, including advanced chemoresistant ovarian cancer. With the use of radiation therapy, which enhances the systemic anti-tumor immune response, immune checkpoint blockade may be a promising therapeutic strategy for distant metastasis, including skin metastasis. Full article

(This article belongs to the Special Issue Ovarian Cancer Metastasis)

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16 pages, 1181 KiB

Open AccessReview

Role of the Exosome in Ovarian Cancer Progression and Its Potential as a Therapeutic Target

by Koji Nakamura, Kenjiro Sawada, Masaki Kobayashi, Mayuko Miyamoto, Aasa Shimizu, Misa Yamamoto, Yasuto Kinose and Tadashi Kimura

Cancers 2019, 11(8), 1147; https://doi.org/10.3390/cancers11081147 - 10 Aug 2019

Cited by 50 | Viewed by 6390

Abstract

Peritoneal dissemination is a distinct form of metastasis in ovarian cancer that precedes hematogenic or lymphatic metastasis. Exosomes are extracellular vesicles of 30–150 nm in diameter secreted by different cell types and internalized by target cells. There is emerging evidence that exosomes facilitate [...] Read more.

Peritoneal dissemination is a distinct form of metastasis in ovarian cancer that precedes hematogenic or lymphatic metastasis. Exosomes are extracellular vesicles of 30–150 nm in diameter secreted by different cell types and internalized by target cells. There is emerging evidence that exosomes facilitate the peritoneal dissemination of ovarian cancer by mediating intercellular communication between cancer cells and the tumor microenvironment through the transfer of nucleic acids, proteins, and lipids. Furthermore, therapeutic applications of exosomes as drug cargo delivery are attracting research interest because exosomes are stabilized in circulation. This review highlights the functions of exosomes in each process of the peritoneal dissemination of ovarian cancer and discusses their potential for cancer therapeutics. Full article

(This article belongs to the Special Issue Ovarian Cancer Metastasis)

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19 pages, 877 KiB

Open AccessReview

The Role of Intra-Tumoral Heterogeneity and Its Clinical Relevance in Epithelial Ovarian Cancer Recurrence and Metastasis

by Cai M. Roberts, Carlos Cardenas and Roslyn Tedja

Cancers 2019, 11(8), 1083; https://doi.org/10.3390/cancers11081083 - 30 Jul 2019

Cited by 38 | Viewed by 7338

Abstract

Epithelial ovarian cancer is the deadliest gynecologic cancer, due in large part to recurrent tumors. Recurrences tend to have metastasized, mainly in the peritoneal cavity and developed resistance to the first line chemotherapy. Key to the progression and ultimate lethality of ovarian cancer [...] Read more.

Epithelial ovarian cancer is the deadliest gynecologic cancer, due in large part to recurrent tumors. Recurrences tend to have metastasized, mainly in the peritoneal cavity and developed resistance to the first line chemotherapy. Key to the progression and ultimate lethality of ovarian cancer is the existence of extensive intra-tumoral heterogeneity (ITH). In this review, we describe the genetic and epigenetic changes that have been reported to give rise to different cell populations in ovarian cancer. We also describe at length the contributions made to heterogeneity by both linear and parallel models of clonal evolution and the existence of cancer stem cells. We dissect the key biological signals from the tumor microenvironment, both directly from other cell types in the vicinity and soluble or circulating factors. Finally, we discuss the impact of tumor heterogeneity on the choice of therapeutic approaches in the clinic. Variability in ovarian tumors remains a major barrier to effective therapy, but by leveraging future research into tumor heterogeneity, we may be able to overcome this barrier and provide more effective, personalized therapy to patients. Full article

(This article belongs to the Special Issue Ovarian Cancer Metastasis)

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17 pages, 1011 KiB

Open AccessReview

Dual Actions of Ketorolac in Metastatic Ovarian Cancer

by Laurie G. Hudson, Linda S. Cook, Martha M. Grimes, Carolyn Y. Muller, Sarah F. Adams and Angela Wandinger-Ness

Cancers 2019, 11(8), 1049; https://doi.org/10.3390/cancers11081049 - 24 Jul 2019

Cited by 17 | Viewed by 4678

Abstract

Cytoreductive surgery and chemotherapy are cornerstones of ovarian cancer treatment, yet disease recurrence remains a significant clinical issue. Surgery can release cancer cells into the circulation, suppress anti-tumor immunity, and induce inflammatory responses that support the growth of residual disease. Intervention within the [...] Read more.

Cytoreductive surgery and chemotherapy are cornerstones of ovarian cancer treatment, yet disease recurrence remains a significant clinical issue. Surgery can release cancer cells into the circulation, suppress anti-tumor immunity, and induce inflammatory responses that support the growth of residual disease. Intervention within the peri-operative window is an under-explored opportunity to mitigate these consequences of surgery and influence the course of metastatic disease to improve patient outcomes. One drug associated with improved survival in cancer patients is ketorolac. Ketorolac is a chiral molecule administered as a 1:1 racemic mixture of the S- and R-enantiomers. The S-enantiomer is considered the active component for its FDA indication in pain management with selective activity against cyclooxygenase (COX) enzymes. The R-enantiomer has a previously unrecognized activity as an inhibitor of Rac1 (Ras-related C3 botulinum toxin substrate) and Cdc42 (cell division control protein 42) GTPases. Therefore, ketorolac differs from other non-steroidal anti-inflammatory drugs (NSAIDs) by functioning as two distinct pharmacologic entities due to the independent actions of each enantiomer. In this review, we summarize evidence supporting the benefits of ketorolac administration for ovarian cancer patients. We also discuss how simultaneous inhibition of these two distinct classes of targets, COX enzymes and Rac1/Cdc42, by S-ketorolac and R-ketorolac respectively, could each contribute to anti-cancer activity. Full article

(This article belongs to the Special Issue Ovarian Cancer Metastasis)

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17 pages, 546 KiB

Open AccessReview

Rare Distant Metastatic Disease of Ovarian and Peritoneal Carcinomatosis: A Review of the Literature

by Nikolaos Thomakos, Michail Diakosavvas, Nikolaos Machairiotis, Zacharias Fasoulakis, Paul Zarogoulidis and Alexandros Rodolakis

Cancers 2019, 11(8), 1044; https://doi.org/10.3390/cancers11081044 - 24 Jul 2019

Cited by 42 | Viewed by 5946

Abstract

Background: Although metastases of ovarian and peritoneal carcinomatosis are most commonly found within the peritoneal cavity, there is a number of other rare distant sites that have been reported. Our goal is to provide an evidence-based summary of the available literature considering the [...] Read more.

Background: Although metastases of ovarian and peritoneal carcinomatosis are most commonly found within the peritoneal cavity, there is a number of other rare distant sites that have been reported. Our goal is to provide an evidence-based summary of the available literature considering the rare distant metastatic sites of ovarian and peritoneal carcinomatosis. Methods: A comprehensive search of the literature was conducted, with Medline/PubMed being searched for cases of rare metastatic disease originated from primary ovarian and peritoneal cancer with related articles up to 2019 including terms such as “ovarian cancer”, “metastases”, “peritoneal” and others. Results: The most common mechanism of ovarian cancer metastases consists of primarily dissemination within the peritoneal cavity, while, rare and distant sites can either occur at the beginning or during the course of the disease and they are usually associated with hematogenous route and lymphatic invasion, having poor prognosis, with the least common sites being skin, bone, CNS, eye, placenta, central airways, rare lymph nodes, intra-abdominal organs, heart and breast. Conclusions: The occurrence of metastatic sites described in this review represents the most common rare distant metastatic sites, and even though their patterns of metastases are still not fully clarified due to the rarity of the reports, they offer valuable information considering the pathophysiology of the disease. Full article

(This article belongs to the Special Issue Ovarian Cancer Metastasis)

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22 pages, 1440 KiB

Open AccessReview

The Role of Cancer Stem Cells and Mechanical Forces in Ovarian Cancer Metastasis

by Michael E. Bregenzer, Eric N. Horst, Pooja Mehta, Caymen M. Novak, Taylor Repetto and Geeta Mehta

Cancers 2019, 11(7), 1008; https://doi.org/10.3390/cancers11071008 - 18 Jul 2019

Cited by 51 | Viewed by 7051

Abstract

Ovarian cancer is an extremely lethal gynecologic disease; with the high-grade serous subtype predominantly associated with poor survival rates. Lack of early diagnostic biomarkers and prevalence of post-treatment recurrence, present substantial challenges in treating ovarian cancers. These cancers are also characterized by a [...] Read more.

Ovarian cancer is an extremely lethal gynecologic disease; with the high-grade serous subtype predominantly associated with poor survival rates. Lack of early diagnostic biomarkers and prevalence of post-treatment recurrence, present substantial challenges in treating ovarian cancers. These cancers are also characterized by a high degree of heterogeneity and protracted metastasis, further complicating treatment. Within the ovarian tumor microenvironment, cancer stem-like cells and mechanical stimuli are two underappreciated key elements that play a crucial role in facilitating these outcomes. In this review article, we highlight their roles in modulating ovarian cancer metastasis. Specifically, we outline the clinical relevance of cancer stem-like cells, and challenges associated with their identification and characterization and summarize the ways in which they modulate ovarian cancer metastasis. Further, we review the mechanical cues in the ovarian tumor microenvironment, including, tension, shear, compression and matrix stiffness, that influence (cancer stem-like cells and) metastasis in ovarian cancers. Lastly, we outline the challenges associated with probing these important modulators of ovarian cancer metastasis and provide suggestions for incorporating these cues in basic biology and translational research focused on metastasis. We conclude that future studies on ovarian cancer metastasis will benefit from the careful consideration of mechanical stimuli and cancer stem cells, ultimately allowing for the development of more effective therapies. Full article

(This article belongs to the Special Issue Ovarian Cancer Metastasis)

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22 pages, 1471 KiB

Open AccessReview

Ovarian Cancer Stem Cells: Role in Metastasis and Opportunity for Therapeutic Targeting

by Xingyue Zong and Kenneth P. Nephew

Cancers 2019, 11(7), 934; https://doi.org/10.3390/cancers11070934 - 03 Jul 2019

Cited by 44 | Viewed by 6017

Abstract

Ovarian cancer (OC) is a heterogeneous disease usually diagnosed at a late stage. Cancer stem cells (CSCs) that exist within the bulk tumor survive first-line chemotherapy and contribute to resistant disease with metastasis. Understanding the key features of CSC biology provides valuable opportunities [...] Read more.

Ovarian cancer (OC) is a heterogeneous disease usually diagnosed at a late stage. Cancer stem cells (CSCs) that exist within the bulk tumor survive first-line chemotherapy and contribute to resistant disease with metastasis. Understanding the key features of CSC biology provides valuable opportunities to develop OCSC-directed therapeutics, which will eventually improve the clinical outcomes of patients. Although significant developments have occurred since OCSCs were first described, the involvement of CSCs in ovarian tumor metastasis is not fully understood. Here, we discuss putative CSC markers and the fundamental role of CSCs in facilitating tumor dissemination in OC. Additionally, we focus on promising CSC-targeting strategies in preclinical and clinical studies of OC and discuss potential challenges in CSC research. Full article

(This article belongs to the Special Issue Ovarian Cancer Metastasis)

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14 pages, 1021 KiB

Open AccessReview

Ovarian Cancer Stemness: Biological and Clinical Implications for Metastasis and Chemotherapy Resistance

by Takeshi Motohara and Hidetaka Katabuchi

Cancers 2019, 11(7), 907; https://doi.org/10.3390/cancers11070907 - 28 Jun 2019

Cited by 37 | Viewed by 7574

Abstract

Epithelial ovarian cancer is a highly lethal gynecological malignancy that is characterized by the early development of disseminated metastasis. Though ovarian cancer has been generally considered to preferentially metastasize via direct transcoelomic dissemination instead of the hematogenous route, emerging evidence has indicated that [...] Read more.

Epithelial ovarian cancer is a highly lethal gynecological malignancy that is characterized by the early development of disseminated metastasis. Though ovarian cancer has been generally considered to preferentially metastasize via direct transcoelomic dissemination instead of the hematogenous route, emerging evidence has indicated that the hematogenous spread of cancer cells plays a larger role in ovarian cancer metastasis than previously thought. Considering the distinctive biology of ovarian cancer, an in-depth understanding of the biological and molecular mechanisms that drive metastasis is critical for developing effective therapeutic strategies against this fatal disease. The recent “cancer stem cell theory” postulates that cancer stem cells are principally responsible for tumor initiation, metastasis, and chemotherapy resistance. Even though the hallmarks of ovarian cancer stem cells have not yet been completely elucidated, metastasized ovarian cancer cells, which have a high degree of chemoresistance, seem to manifest cancer stem cell properties and play a key role during relapse at metastatic sites. Herein, we review our current understanding of the cell-biological mechanisms that regulate ovarian cancer metastasis and chemotherapy resistance, with a pivotal focus on ovarian cancer stem cells, and discuss the potential clinical implications of evolving cancer stem cell research and resultant novel therapeutic approaches. Full article

(This article belongs to the Special Issue Ovarian Cancer Metastasis)

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10 pages, 500 KiB

Open AccessReview

B Cells as an Immune-Regulatory Signature in Ovarian Cancer

by Prachi Gupta, Changliang Chen, Pradeep Chaluvally-Raghavan and Sunila Pradeep

Cancers 2019, 11(7), 894; https://doi.org/10.3390/cancers11070894 - 26 Jun 2019

Cited by 35 | Viewed by 4666

Abstract

Increasing evidence suggests that the immune system plays a dynamic role in the progression of ovarian cancer, the deadliest gynecological malignancy worldwide. Accumulation of tumor-infiltrating lymphocytes has been associated with increased survival in ovarian cancer patients, and diverse interactions among immune cells in [...] Read more.

Increasing evidence suggests that the immune system plays a dynamic role in the progression of ovarian cancer, the deadliest gynecological malignancy worldwide. Accumulation of tumor-infiltrating lymphocytes has been associated with increased survival in ovarian cancer patients, and diverse interactions among immune cells in the tumor microenvironment determine tumor progression. While the regulatory functions of T cells among tumor-infiltrating lymphocytes are well defined and also involve therapeutic interventions, the role of B cells in ovarian cancer progression is still limited to their impact on survival. Recent studies have identified both pro- and anti-tumor responses of B cells in solid tumors, as different subsets of B cells play diverse roles in progression. Thus, in-depth characterization of B cell subtypes in each disease stage is crucial for understanding the importance and therapeutic potential of these cells in ovarian cancer. In this review, we summarize current knowledge about B cells in ovarian cancer and discuss emerging therapeutic interventions that could harness B cells to combat this deadly disease. Full article

(This article belongs to the Special Issue Ovarian Cancer Metastasis)

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