Obesity Contributes to Ovarian Cancer Metastatic Success through Increased Lipogenesis, Enhanced Vascularity, and Decreased Infiltration of M1 Macrophages.

Published on Dec 1, 2015in Cancer Research9.727
· DOI :10.1158/0008-5472.CAN-15-0706
Yueying Liu16
Estimated H-index: 16
(ND: University of Notre Dame),
Matthew N. Metzinger3
Estimated H-index: 3
(ND: University of Notre Dame)
+ 19 AuthorsM. Sharon Stack17
Estimated H-index: 17
(ND: University of Notre Dame)
Sources
Abstract
Epithelial ovarian cancer (EOC) is the leading cause of death from gynecologic malignancy, with high mortality attributable to widespread intraperitoneal metastases. Recent meta-analyses report an association between obesity, ovarian cancer incidence, and ovarian cancer survival, but the effect of obesity on metastasis has not been evaluated. The objective of this study was to use an integrative approach combining in vitro , ex vivo , and in vivo studies to test the hypothesis that obesity contributes to ovarian cancer metastatic success. Initial in vitro studies using three-dimensional mesomimetic cultures showed enhanced cell–cell adhesion to the lipid-loaded mesothelium. Furthermore, in an ex vivo colonization assay, ovarian cancer cells exhibited increased adhesion to mesothelial explants excised from mice modeling diet-induced obesity (DIO), in which they were fed a “Western” diet. Examination of mesothelial ultrastructure revealed a substantial increase in the density of microvilli in DIO mice. Moreover, enhanced intraperitoneal tumor burden was observed in overweight or obese animals in three distinct in vivo models. Further histologic analyses suggested that alterations in lipid regulatory factors, enhanced vascularity, and decreased M1/M2 macrophage ratios may account for the enhanced tumorigenicity. Together, these findings show that obesity potently affects ovarian cancer metastatic success, which likely contributes to the negative correlation between obesity and ovarian cancer survival. Cancer Res; 75(23); 5046–57. ©2015 AACR .
📖 Papers frequently viewed together
1,086 Citations
1,030 Citations
34.9k Citations
References51
Newest
#1Kyle A. Lewellen (ND: University of Notre Dame)H-Index: 2
#2Matthew N. Metzinger (ND: University of Notre Dame)H-Index: 3
Last. M. Sharon Stack (ND: University of Notre Dame)H-Index: 17
view all 4 authors...
Epithelial ovarian cancer (EOC) is the leading cause of death from gynecologic malignancy in the United States. Mortality is due to diagnosis of 75% of women with late stage disease, when metastasis is already present. EOC is characterized by diffuse and widely disseminated intra-peritoneal metastasis. Cells shed from the primary tumor anchor in the mesothelium that lines the peritoneal cavity as well as in the omentum, resulting in multi-focal metastasis, often in the presence of peritoneal asc...
9 CitationsSource
#1Lana BruneyH-Index: 3
#2Kaitlynn C. ConleyH-Index: 1
Last. M. Sharon Stack (ND: University of Notre Dame)H-Index: 17
view all 5 authors...
Mucin16 (MUC16/cancer antigen 125 (CA-125)), a high-molecular-weight glycoprotein expressed on the ovarian tumor cell surface, potentiates metastasis via selective binding to mesothelin on peritoneal mesothelial cells. Shed MUC16/CA-125 is detectable in sera from ovar - ian cancer patients. We investigated the potential role of membrane type 1 matrix metalloproteinase (MT1-MMP, MMP-14), a transmembrane collagenase highly expressed in ovarian cancer cells, in MUC16/CA-125 ectodomain shedding. An ...
22 CitationsSource
#1Joellen M. Schildkraut (Duke University)H-Index: 83
#2Anthony J. Alberg (MUSC: Medical University of South Carolina)H-Index: 69
Last. Patricia G. Moorman (Duke University)H-Index: 57
view all 15 authors...
Background Ovarian cancer (OVCA) is the leading cause of death from gynecological cancer, with poorer survival for African American (AA) women compared to whites. However, little is known about risk factors for OVCA in AA. To study the epidemiology of OVCA in this population, we started a collaborative effort in 10 sites in the US. Here we describe the study and highlight the challenges of conducting a study of a lethal disease in a minority population.
43 CitationsSource
#1Elena B. Lomakina (UR: University of Rochester)H-Index: 10
#2Graham Marsh (UR: University of Rochester)H-Index: 11
Last. Richard E. Waugh (UR: University of Rochester)H-Index: 40
view all 3 authors...
Adhesive interactions between neutrophils and endothelium involve chemokine-induced neutrophil spreading and subsequent crawling on the endothelium to sites of transmigration. We investigated the importance of cell topography in this process using immunofluorescence, scanning electron microscopy, and live-cell imaging using total internal reflectance microscopy to observe redistribution of key membrane proteins, both laterally and relative to surface topography, during neutrophil spreading onto ...
15 CitationsSource
#1Jiyoung Park (UNIST: Ulsan National Institute of Science and Technology)H-Index: 37
#2Thomas S. Morley (UNIST: Ulsan National Institute of Science and Technology)H-Index: 10
Last. Philipp E. Scherer (UNIST: Ulsan National Institute of Science and Technology)H-Index: 147
view all 5 authors...
Obesity is associated with an increased risk of certain cancers, such as breast and colon cancers and hepatocellular carcinoma. In this Review, the authors discuss the mechanisms that underlie the interplay between tumour cells and adipocyte-rich stromal tissues that drives the creation and maintenance of a unique microenvironment that favours tumour growth and metastasis.
322 CitationsSource
#1Ernst Lengyel (U of C: University of Chicago)H-Index: 67
#2Joanna E. Burdette (UIC: University of Illinois at Chicago)H-Index: 31
Last. M. Stack (ND: University of Notre Dame)H-Index: 2
view all 9 authors...
Epithelial ovarian cancer (OvCa) is associated with high mortality and, as the majority (>75%) of women with OvCa have metastatic disease at the time of diagnosis, rates of survival have not changed appreciably over 30 years. A mechanistic understanding of OvCa initiation and progression is hindered by the complexity of genetic and/or environmental initiating events and lack of clarity regarding the cell(s) or tissue(s) of origin. Metastasis of OvCa involves direct extension or exfoliation of ce...
132 CitationsSource
#1Emily K. Colvin (Kolling Institute of Medical Research)H-Index: 20
Ovarian cancer is the leading cause of death in women with gynecological malignancy and improvements in current treatments are needed. As with many other solid cancers, the ovarian tumor microenvironment is emerging as a key player in tumor progression and a potential therapeutic target. The tumor microenvironment contains several non-malignant cell types that are known to contribute to tumor progression and metastasis. Included in this population of non-malignant cells are several different typ...
91 CitationsSource
#1Calvin Tebbe (HFH: Henry Ford Hospital)H-Index: 6
#2Jasdeep Chhina (HFH: Henry Ford Hospital)H-Index: 8
Last. Ramandeep Rattan (HFH: Henry Ford Hospital)H-Index: 29
view all 7 authors...
// Calvin Tebbe 1 , Jasdeep Chhina 1 , Sajad A. Dar 1 , Kalli Sarigiannis 1 , Shailendra Giri 2 , Adnan R. Munkarah 1 , and Ramandeep Rattan 1 1 Division of Gynecology Oncology, Department of Women’s Health, Obstetrics and Gynecology, Henry Ford Hospital, Detroit, MI 48202, USA. 2 Department of Neurology, Henry Ford Hospital, Detroit, MI, USA. Correspondence: Ramandeep Rattan, email: // Keywords : ovarian cancer, 3T3L1 adipocytes, metformin, AMPK, ID8 cells, adipogenesis Received : March 6, 2014...
51 CitationsSource
#1Deliang GuoH-Index: 24
#2Erica Hlavin BellH-Index: 14
Last. Arnab Chakravarti (James Cancer Hospital)H-Index: 56
view all 4 authors...
Metabolic reprogramming is a hallmark of cancer. Oncogenic growth signaling regulates glucose, glutamine and lipid metabolism to meet the bioenergetics and biosynthetic demands of rapidly proliferating tumor cells. Emerging evidence indicates that sterol regulatory element-binding protein 1 (SREBP-1), a master transcription factor that controls lipid metabolism, is a critical link between oncogenic signaling and tumor metabolism. We recently demonstrated that SREBP-1 is required for the survival...
127 CitationsSource
#1Hyo Sook Bae (KU: Korea University)H-Index: 9
#2Hyun Jung Kim (KU: Korea University)H-Index: 57
Last. Jae Yun Song (KU: Korea University)H-Index: 11
view all 6 authors...
Background Studies on the association between obesity and ovarian cancer survival have had conflicting results. We reviewed and quantitatively summarized the existing evidence, exploring potentially important sources of variability, such as the timing of body mass index (BMI) assessment, BMI cut points, references used in multivariate analysis, and ovarian cancer stage.
41 CitationsSource
Cited By48
Newest
#1Yuanyuan An (PRC: China Medical University (PRC))
#2Qing Yang (PRC: China Medical University (PRC))
Ovarian cancer is one of the most common gynecological malignancies. The tumor microenvironment plays an important role in regulating the progression of ovarian cancer. Macrophages, which are important immune cells in the tumor microenvironment, participate in the regulation of various biological behaviors and influence the prognosis of ovarian cancer. A large number of studies have targeted macrophages for the treatment of ovarian cancer. In addition, macrophages also play a regulatory role by ...
Source
#1Saleha Anwar (Jamia Millia Islamia)H-Index: 8
#2Anas Shamsi (Jamia Millia Islamia)H-Index: 14
Last. Md. Imtaiyaz Hassan (Jamia Millia Islamia)H-Index: 35
view all 5 authors...
Pyruvate is irreversibly decarboxylated to acetyl coenzyme A by mitochondrial pyruvate dehydrogenase complex (PDC). Decarboxylation of pyruvate is considered a crucial step in cell metabolism and energetics. The cancer cells prefer aerobic glycolysis rather than mitochondrial oxidation of pyruvate. This attribute of cancer cells allows them to sustain under indefinite proliferation and growth. Pyruvate dehydrogenase kinases (PDKs) play critical roles in many diseases because they regulate PDC ac...
Source
#1Shasha HouH-Index: 1
#2Qi Yuan (Beijing Jiaotong University)H-Index: 1
Last. Xiaxia YuanH-Index: 1
view all 6 authors...
Alpinetin (ALP) has been reported to act as an anticancer agent. This study was carried out to elucidate the effect of ALP on high-fat diet (HFD)-induced aggressive cancer progression. C57BL/6 mice were fed with a control diet (CD) or HFD and administered with ALP. Following 6 weeks of feeding, mice were inoculated subcutaneously with Lewis lung carcinoma cells (LLC) to develop transplanted lung tumour. ALP suppressed cell proliferation which drives HFD-induced lung cancer progression. ALP inhib...
Source
#1Michael S. SimonH-Index: 52
Last. Nida Waheed (UF: University of Florida)H-Index: 3
view all 21 authors...
BACKGROUND: Few studies have examined the relationship between cardiometabolic risk factors linked to metabolic syndrome and mortality among women with breast cancer. METHODS: We used the Women's Health Initiative to evaluate the relationship between cardiometabolic risk factors, including waist circumference (WC), blood pressure, cholesterol level, and presence of type 2 diabetes, and their relation with death from breast cancer, cardiovascular disease (CVD), and other causes among 8641 women w...
14 CitationsSource
#1Jing Yang (ND: University of Notre Dame)H-Index: 6
#2M. Sharon Stack (ND: University of Notre Dame)H-Index: 17
Last. M. Sharon Stack (ND: University of Notre Dame)H-Index: 18
view all 2 authors...
Obesity has become a recognized global epidemic that is associated with numerous comorbidities including type II diabetes, cardiovascular disease, hypertension, and cancer incidence and progression. Ovarian cancer (OvCa) has a unique mechanism of intra-peritoneal metastasis, already present in 80% of women at the time of diagnosis, making it the fifth leading cause of death from gynecological malignancy. Meta-analyses showed that obesity increases the risk of OvCa progression, leads to enhanced ...
2 CitationsSource
Ovarian cancer cells mainly metastasise within the peritoneal cavity, the lethal consequence of tumour progression in this cancer type. Classically, changes in tumour cells, such as epithelial to mesenchymal transition, involve the down-regulatinon of E-cadherin, activation of extracellular proteases and integrin-mediated adhesion. However, our current understanding of ovarian tumour progression suggests the implication of both intrinsic and extrinsic factors. It has been proposed that ovarian c...
Source
#1Nicole E JamesH-Index: 4
#2Morgan WoodmanH-Index: 1
Last. Jennifer R. RibeiroH-Index: 8
view all 4 authors...
Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy, with an overall 5-year survival of only 47%. As the development of novel targeted therapies is drastically necessary in order to improve patient survival, current EOC clinical trials have heavily focused on immunotherapeutic approaches, centered upon programmed cell death 1 (PD-1) inhibitors. While PD-1 monotherapies have only exhibited modest responses for patients, it has been theorized that in order to enhance EOC pati...
1 CitationsSource
#1Marwa Asem (ND: University of Notre Dame)H-Index: 5
#2Allison Young (ND: University of Notre Dame)H-Index: 2
Last. M. Sharon Stack (ND: University of Notre Dame)H-Index: 18
view all 10 authors...
The majority of women with recurrent ovarian cancer (OvCa) develop malignant ascites with volumes that can reach > 2 L. The resulting elevation in intraperitoneal pressure (IPP), from normal values of 5 mmHg to as high as 22 mmHg, causes striking changes in the loading environment in the peritoneal cavity. The effect of ascites-induced changes in IPP on OvCa progression is largely unknown. Herein we model the functional consequences of ascites-induced compression on ovarian tumor cells and compo...
8 CitationsSource
#1Yousef Yousefzadeh (Tabriz University of Medical Sciences)H-Index: 6
#1Yousef Yousefzadeh (Tabriz University of Medical Sciences)H-Index: 3
Last. Farhad Jadidi-Niaragh (Tabriz University of Medical Sciences)H-Index: 37
view all 8 authors...
Abstract The tumor microenvironment is a critical factor that enhances cancer progression, drug resistance, and failure of therapeutic approaches. Several cellular and non-cellular factors are involved in cancer promotion. Among the several cell populations in the tumor microenvironment, macrophages, as one of the most abundant innate immune cells within the tumor milieu, have attracted extensive attention among several researchers because of their critical role in innate pathophysiology of mult...
7 CitationsSource
#1Paul WeiheH-Index: 2
#2Julia Spielmann (MLU: Martin Luther University of Halle-Wittenberg)H-Index: 13
Last. Susann Weihrauch-BlüherH-Index: 4
view all 5 authors...
PURPOSE OF REVIEW The purpose of this review is to summarize our current understanding of the association between childhood obesity and cancer risk later in life. RECENT FINDINGS Adipose tissue secrets a variety of adipocytokines, and expression and/or secretion rate of most of them seems to be increased or dysregulated in obesity. In addition, obesity leads to increased secretion of proinflammatory cytokines such as interferon-γ (IFN-γ), interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α)...
3 CitationsSource