Lysophosphatidic acid modulates ovarian cancer multicellular aggregate assembly and metastatic dissemination.

Published on Jul 2, 2020in Scientific Reports3.998
· DOI :10.1038/S41598-020-67565-7
Yuliya Klymenko8
Estimated H-index: 8
(IU: Indiana University),
Brandi Bos1
Estimated H-index: 1
(ND: University of Notre Dame)
+ 5 AuthorsM. Sharon Stack17
Estimated H-index: 17
(ND: University of Notre Dame)
Epithelial ovarian cancer (EOC) metastasis occurs by exfoliation of cells and multicellular aggregates (MCAs) from the tumor into the peritoneal cavity, adhesion to and retraction of peritoneal mesothelial cells and subsequent anchoring. Elevated levels of lysophosphatidic acid (LPA) have been linked to aberrant cell proliferation, oncogenesis, and metastasis. LPA disrupts junctional integrity and epithelial cohesion in vitro however, the fate of free-floating cells/MCAs and the response of host peritoneal tissues to LPA remain unclear. EOC MCAs displayed significant LPA-induced changes in surface ultrastructure with the loss of cell surface protrusions and poor aggregation, resulting in increased dissemination of small clusters compared to untreated control MCAs. LPA also diminished the adhesive capacity of EOC single cells and MCAs to murine peritoneal explants and impaired MCA survival and mesothelial clearance competence. Peritoneal tissues from healthy mice injected with LPA exhibited enhanced mesothelial surface microvilli. Ultrastructural alterations were associated with restricted peritoneal susceptibility to metastatic colonization by single cells as well as epithelial-type MCAs. The functional consequence is an LPA-induced dissemination of small mesenchymal-type clusters, promoting a miliary mode of peritoneal seeding that complicates surgical removal and is associated with worse prognosis.
📖 Papers frequently viewed together
3 Citations
9 Authors (Juan Ren, ..., Yan Xu)
224 Citations
31 Citations
#1Shohreh Azadi (UTS: University of Technology, Sydney)H-Index: 8
#2Hamidreza Aboulkheyr Es (UTS: University of Technology, Sydney)H-Index: 5
Last. Majid Ebrahimi Warkiani (UTS: University of Technology, Sydney)H-Index: 33
view all 6 authors...
Abstract Expression of programmed death-ligand 1 (PD-L1) in cancer cells plays an important role in cancer-immune cell interaction. The emerging evidence suggests regulation of PD-L1 expression by several tumor microenvironmental cues. However, the association of PD-L1 expression with chemical and mechanical features of the tumor microenvironment, specifically epidermal growth factor receptor (EGFR) signaling and matrix stiffness, remains elusive. Herein, we determine whether EGFR targeting and ...
13 CitationsSource
#1Christiaan F. Labuschagne (Francis Crick Institute)H-Index: 13
#2Eric C. Cheung (Francis Crick Institute)H-Index: 17
Last. Karen H. Vousden (Francis Crick Institute)H-Index: 107
view all 5 authors...
Summary Cancer metastasis depends on cell survival following loss of extracellular matrix attachment and dissemination through the circulation. The metastatic spread can be enhanced by the clustering of detached cancer cells and increased antioxidant defense. Here, we link these responses by describing how cell clustering limits reactive oxygen species (ROS). Loss of attachment causes mitochondrial perturbations and increased ROS production. The formation of cell clusters induces a hypoxic envir...
40 CitationsSource
#1Veena Padmanaban (Johns Hopkins University)H-Index: 6
#2Ilona Krol (University of Basel)H-Index: 9
Last. Andrew J. Ewald (Johns Hopkins University)H-Index: 39
view all 7 authors...
Metastasis is the major driver of death in patients with cancer. Invasion of surrounding tissues and metastasis have been proposed to initiate following loss of the intercellular adhesion protein, E-cadherin1,2, on the basis of inverse correlations between in vitro migration and E-cadherin levels3. However, this hypothesis is inconsistent with the observation that most breast cancers are invasive ductal carcinomas and express E-cadherin in primary tumours and metastases4. To resolve this discrep...
174 CitationsSource
#1Yiting Sun (SDU: Shandong University)H-Index: 3
#2Song Li (SDU: Shandong University)H-Index: 3
Last. Lian Liu (SDU: Shandong University)H-Index: 3
view all 7 authors...
: Peritoneal metastasis is the most common pathway for the spread of ovarian cancer and one of the major causes of cancer death. Ovarian cancer cells in ascites prefer to aggregate into the multicellular spheroids (MCS) with an inadequate response to chemotherapy. In this study, gene expression analysis implicated that ovarian cancer MCS had its unique expression pattern and the cell cycle-related pathways were prominently altered in MCS cells compared to the monolayer adherent cells. Flow cytom...
6 CitationsSource
#1Qingyu Zhang (UM: University of Macau)H-Index: 3
#2Shan Yu (UM: University of Macau)H-Index: 5
Last. Leo T. O. Lee (UM: University of Macau)H-Index: 18
view all 8 authors...
Background Angiotensin II (ANGII) and its receptor (AGTR1) have been proposed as significant contributors to metastasis in multiple cancers. Further, high AGTR1 levels are associated with poor epithelial ovarian cancer (EOC) outcomes. However, the mechanistic basis for these effects is unknown. Recent studies have suggested that ovarian cancer metastasis is highly dependent on the formation of multicellular spheroids (MCS). To understand the associations between the ANGII/AGTR1 pathway and cance...
15 CitationsSource
#1Silke ReinartzH-Index: 19
#2Sonja LieberH-Index: 9
Last. Rolf MüllerH-Index: 118
view all 18 authors...
: The peritoneal fluid of ovarian carcinoma patients promotes cancer cell invasion and metastatic spread with lysophosphatidic acid (LPA) as a potentially crucial mediator. However, the origin of LPA in ascites and the clinical relevance of individual LPA species have not been addressed. Here, we show that the levels of multiple acyl-LPA species are strongly elevated in ascites versus plasma and are associated with short relapse-free survival. Data derived from transcriptome and secretome analys...
15 CitationsSource
#1Ana S. NunesH-Index: 3
#2Andreia S. BarrosH-Index: 3
Last. Ilídio J. Correia (UC: University of Coimbra)H-Index: 53
view all 5 authors...
: Three-dimensional cell culture models, such as spheroids, can be used in the process of the development of new anticancer agents because they are able to closely mimic the main features of human solid tumors, namely their structural organization, cellular layered assembling, hypoxia, and nutrient gradients. These properties imprint to the spheroids an anticancer therapeutics resistance profile, which is similar to that displayed by human solid tumors. In this review, an overview of the drug re...
142 CitationsSource
#1Joelle Sacks Suarez (UIC: University of Illinois at Chicago)H-Index: 1
#2Hilal Gurler Main (UIC: University of Illinois at Chicago)H-Index: 1
Last. Maria V. Barbolina (UIC: University of Illinois at Chicago)H-Index: 20
view all 7 authors...
Disseminating epithelial ovarian cancer cells often become assembled into spheroids prior to their arrival at metastatic sites within the peritoneal cavity. Although epithelial ovarian carcinoma is the deadliest gynecologic malignancy, the mechanisms regulating formation and metastatic potential of spheroids are poorly understood. We show that expression of a cell surface glycoprotein CD44 is an important contributing factor for spheroid formation and spheroid adhesion to mesothelial cells, and ...
5 CitationsSource
#1Lin Gong (Sichuan University)H-Index: 3
#2Ying Zheng (Sichuan University)H-Index: 4
Last. Zhi-lan Peng (Sichuan University)H-Index: 7
view all 4 authors...
: Objective: To investigate the regulatory role of fibronectin (FN) in the formation of multicellular aggregate (MCA) in ovarian cancer SKOV3 and OVCAR-3 cells and integrin expression. Methods: The dynamic formation of MCA in SKOV3 and OVCAR-3 was determined using the liquid overlay technique in the presence or absence of FN, anti-FN, RGD peptide, control RGE. The expression of α3β1, α4β1 and α5β1 integrin in monolayer cells, MCA and FN-treated MCA were determined by flow cytometry and quantitat...
5 CitationsSource
#1Yukiko Miyatake (Hokkaido University)H-Index: 11
#2Yusuke Ohta (Hokkaido University)H-Index: 1
Last. Masanori Kasahara (Hokkaido University)H-Index: 62
view all 4 authors...
// Yukiko Miyatake 1, * , Yusuke Ohta 1, * , Shunji Ikeshita 1 and Masanori Kasahara 1 1 Department of Pathology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, 060-8638, Japan * These authors contributed equally to this work Correspondence to: Yukiko Miyatake, email: Keywords: pancreatic cancer; collective cell behavior; Ad-MCA; coculture; HEK293T; Pathology Received: May 22, 2018 Accepted: June 24, 2018 Published: July 06, 2018 ABS...
1 CitationsSource
Cited By1