Milky Spots Promote Ovarian Cancer Metastatic Colonization of Peritoneal Adipose in Experimental Models

Clark, R. J. H.; Krishnan, Venkatesh; Schoof, Michael; Rodriguez, Irving; Theriault, Betty; Chekmareva, Marina; Rinker‐Schaeffer, Carrie W.

doi:10.1016/j.ajpath.2013.04.023

Cited by 125 publications

(145 citation statements)

References 53 publications

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“…Recently, we showed that O-ASCs promoted proliferation, migration, chemotherapy, and radiation response of ovarian cancer cells (8). Omentum has been shown to promote colonization of ovarian cancer cells (11). Mounting evidence suggests that bidirectional communication between ovarian cancer and its microenvironment is critical for tumor growth (12).…”

Section: Introductionmentioning

confidence: 99%

Nitric Oxide Mediates Metabolic Coupling of Omentum-Derived Adipose Stroma to Ovarian and Endometrial Cancer Cells

et al. 2015

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Omental adipose stromal cells (O-ASC) are a multipotent population of mesenchymal stem cells contained in the omentum tissue that promote endometrial and ovarian tumor proliferation, migration, and drug resistance. The mechanistic underpinnings of O-ASCs' role in tumor progression and growth are unclear. Here, we propose a novel nitric oxide (NO)-mediated metabolic coupling between O-ASCs and gynecologic cancer cells in which O-ASCs support NO homeostasis in malignant cells. NO is synthesized endogenously by the conversion of L-arginine into citrulline through nitric oxide synthase (NOS). Through arginine depletion in the media using L-arginase and NOS inhibition in cancer cells using N G -nitro-L-arginine methyl ester (L-NAME), we demonstrate that patientderived O-ASCs increase NO levels in ovarian and endometrial cancer cells and promote proliferation in these cells. O-ASCs and cancer cell cocultures revealed that cancer cells use O-ASCsecreted arginine and in turn secrete citrulline in the microenvironment. Interestingly, citrulline increased adipogenesis potential of the O-ASCs. Furthermore, we found that O-ASCs increased NO synthesis in cancer cells, leading to decrease in mitochondrial respiration in these cells. Our findings suggest that O-ASCs upregulate glycolysis and reduce oxidative stress in cancer cells by increasing NO levels through paracrine metabolite secretion. Significantly, we found that O-ASCmediated chemoresistance in cancer cells can be deregulated by altering NO homeostasis. A combined approach of targeting secreted arginine through L-arginase, along with targeting microenvironment-secreted factors using L-NAME, may be a viable therapeutic approach for targeting ovarian and endometrial cancers. Cancer Res; 75(2); 456-71. Ó2014 AACR.

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Section: Introductionmentioning

confidence: 99%

Nitric Oxide Mediates Metabolic Coupling of Omentum-Derived Adipose Stroma to Ovarian and Endometrial Cancer Cells

et al. 2015

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“…Unlike other peritoneal adipose, omental adipose tissue contains unusual immune structures known as milky spots, which contain B, T, and NK cells and macrophages, which play key roles in peritoneal homeostasis 8,9 . In addition to their physiologic functions, we found that milky spots play an active role in ovarian cancer metastatic colonization 4 . In experimental metastasis assays, SKOV3ip.1, CaOV3, and HeyA8 (human) and ID8 (murine; C57BL/6) ovarian cancer cells rapidly home to milky spots, suggesting that the cells are moving toward a secreted chemotactic factor.…”

mentioning

confidence: 93%

“…The omentum is a preferred early site of HGSC metastasis [4][5][6][7] . Unlike other peritoneal adipose, omental adipose tissue contains unusual immune structures known as milky spots, which contain B, T, and NK cells and macrophages, which play key roles in peritoneal homeostasis 8,9 .…”

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confidence: 99%

“…In experimental metastasis assays, SKOV3ip.1, CaOV3, and HeyA8 (human) and ID8 (murine; C57BL/6) ovarian cancer cells rapidly home to milky spots, suggesting that the cells are moving toward a secreted chemotactic factor. Interestingly, cancer cells do not colonize peritoneal adipose lacking milky spots (i.e., gonadal and uterine fat) 4 .…”

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confidence: 99%

“…In order to identify mechanisms regulating milky spot colonization, we have optimized xenograft models that enable the interrogation of cellular and molecular events over the time course of metastatic colonization 4 . A specific advantage of the approaches described herein is its emphasis on tissue architecture and function, which enables users to test hypotheses in fully integrated in vivo and ex vivo models of metastatic colonization 4,10 .…”

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confidence: 99%

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<em>In Vivo</em> and <em>Ex Vivo</em> Approaches to Study Ovarian Cancer Metastatic Colonization of Milky Spot Structures in Peritoneal Adipose

Krishnan

Clark

Chekmareva

et al. 2015

JoVE

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High-grade serous ovarian cancer (HGSC), the cause of widespread peritoneal metastases, continues to have an extremely poor prognosis; fewer than 30% of women are alive 5 years after diagnosis. The omentum is a preferred site of HGSC metastasis formation. Despite the clinical importance of this microenvironment, the contribution of omental adipose tissue to ovarian cancer progression remains understudied. Omental adipose is unusual in that it contains structures known as milky spots, which are comprised of B, T, and NK cells, macrophages, and progenitor cells surrounding dense nests of vasculature. Milky spots play a key role in the physiologic functions of the omentum, which are required for peritoneal homeostasis. We have shown that milky spots also promote ovarian cancer metastatic colonization of peritoneal adipose, a key step in the development of peritoneal metastases. Here we describe the approaches we developed to evaluate and quantify milky spots in peritoneal adipose and study their functional contribution to ovarian cancer cell metastatic colonization of omental tissues both in vivo and ex vivo. These approaches are generalizable to additional mouse models and cell lines, thus enabling the study of ovarian cancer metastasis formation from initial localization of cells to milky spot structures to the development of widespread peritoneal metastases. Video LinkThe video component of this article can be found at

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Role of tumor microenvironment in the pathobiology of ovarian cancer: Insights and therapeutic opportunities

et al. 2018

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Ovarian cancer is the fifth most common cancer affecting women and at present, stands as the most lethal gynecologic malignancy. The poor disease outcome is due to the nonspecific symptoms and the lack of effective treatment at advanced stages. Thus, it is of utmost importance to understand ovarian carcinoma through several lenses and to dissect the role that the unique peritoneal tumor microenvironment plays in ovarian cancer progression and metastasis. This review seeks to highlight several determinants of this unique tumor microenvironment, their influence on disease outcome and ongoing clinical trials targeting these determinants.

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Milky Spots Promote Ovarian Cancer Metastatic Colonization of Peritoneal Adipose in Experimental Models

Cited by 125 publications

References 53 publications

Nitric Oxide Mediates Metabolic Coupling of Omentum-Derived Adipose Stroma to Ovarian and Endometrial Cancer Cells

Nitric Oxide Mediates Metabolic Coupling of Omentum-Derived Adipose Stroma to Ovarian and Endometrial Cancer Cells

<em>In Vivo</em> and <em>Ex Vivo</em> Approaches to Study Ovarian Cancer Metastatic Colonization of Milky Spot Structures in Peritoneal Adipose

Role of tumor microenvironment in the pathobiology of ovarian cancer: Insights and therapeutic opportunities

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