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Ovarian Cancer Metastases Influenced by Factors in Target Tissues


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Both milky spots and fat cells in omentum promote cancer cell migration, growth, and spread, reports The American Journal of Pathology

Philadelphia, PA

Cancer researchers have wondered why ovarian cancer cells are so attracted to the abdominal cavity, especially the omentum, with the hope that such an understanding could lead to better disease management or even prevention. Results from a series of experiments suggest a two-step model of omental colonization in which i) cancer cells are attracted to and lodge within immune cell-containing structures known as milky spots, and ii) fat storage cells (adipocytes) fuel cancer cell growth and spread. This study is scheduled for publication in the August 2013 issue of The American Journal of Pathology.

The omentum is a large fatty structure that drapes off the stomach and blankets the peritoneal organs. Omental fat is composed of adipocytes, blood vessels, immune cells, and other connective tissue and contains unusual immune cell-containing structures known as milky spots, which play a key role in many of its protective functions. In previous research, investigators focused either on the milky spots or the adipocytes as key to attracting metastatic ovarian cancer cells. The results of the current experiments show that “although there are clear strengths to both of these models, neither address the intimate and dynamic interaction among milky spots, surrounding adipocytes, and other components of omental tissues. We propose an alternative, more fully integrated model,” says Carrie Rinker-Schaeffer, PhD, a professor in the Departments of Surgery (Section of Urology) and Obstetrics and Gynecology at The University of Chicago.

In the first experiment, researchers investigated whether abdominal fat tissue that contains milky spots is a more attractive target for cancer cells than abdominal fat that does not contain milky spots. This study took advantage of the fact that mice have a second source of milky spot-containing abdominal fat (splenoportal fat) as well as fat that is devoid of milky spots (the gonadal, uterine, and mesenteric fat). They found that different ovarian cancer cell lines (mouse derived ID8, and human derived SKOV3ip.1, HeyA8, and CaOV3) specifically colonize omental and splenoportal fat, forming large lesions of cancer cells within milky spots. In contrast, ovarian cancer cells were rarely detected in abdominal fat that lacks milky spots.

The rapid localization of ovarian cancer cells to milky spots indicated that omental tissue secretes a factor, or factors that attract the cancer cells to these structures. Experiments showed that milky-spot-containing tissues in particular can condition cell growth medium to stimulate the migration of cancer cells. This study found that cell medium conditioned by omenta and splenoportal fat caused a 95-fold increase in cell migration, compared to controls. This study also examined mice with specific immunodeficiencies to show that ovarian cancer cell colonization of milky spots is not affected by deficiency or absence of T cells, B cells, and/or NK cells.

The authors also found an inverse relationship between ovarian cancer cell growth and depletion of adipocytes. “These data are consistent with previous reports from other investigators that indicate cancer cells use lipids stored in adipocytes as an energy source for their continued growth,” says Dr. Rinker-Schaeffer. “Certain tumor cells (the ‘seed’) have a proclivity for specific organ microenvironments (the ‘soil’),” adds Dr. Rinker-Schaeffer. “Pioneers of metastasis research appreciated that the unique tissue architecture, physiology, and function of the target organ are essential to understanding metastatic organ specificity. With this in mind, we hope that our findings and discussion of how they fit into the big picture of omental colonization will facilitate studies that continue to improve our understanding of this process.”

In 2012, ovarian cancer was diagnosed in almost 23,000 American women and 16,000 died from the disease. It is estimated that 22,240 women will be diagnosed with and 14,030 women will die of cancer of the ovary in 2013.



Notes for Editors
“Milky spots promote ovarian cancer metastatic colonization of peritoneal adipose in experimental models,” by Robert Clark, Venkatesh Krishnan, Michael Schoof, Irving Rodriguez, Betty Theriault, Marina Chekmareva, and Carrie Rinker-Schaeffer (DOI: http://dx.doi.org/10.1016/j.ajpath.2013.04.023). It appears in The American Journal of Pathology, Volume 183, Issue 2 (August 2013) published by Elsevier.


About The American Journal of Pathology
The American Journal of Pathology (http://ajp.amjpathol.org), official journal of the American Society for Investigative Pathology, seeks to publish high-quality, original papers on the cellular and molecular biology of disease. The editors accept manuscripts that advance basic and translational knowledge of the pathogenesis, classification, diagnosis, and mechanisms of disease, without preference for a specific analytic method. High priority is given to studies on human disease and relevant experimental models using cellular, molecular, animal, biological, chemical, and immunological approaches in conjunction with morphology.

The leading global forum for reporting quality original research on cellular and molecular mechanisms of disease, The American Journal of Pathology is the most highly cited journal in Pathology – over 38,000 cites in 2012 – with an Impact Factor of 4.522 and Eigenfactor of 0.07599 according to the 2012 Journal Citation Reports®, Thomson Reuters, and an H index of 181 according to the 2011 SCImago Journal & Country Rank.

About Elsevier
Elsevier is a world-leading provider of scientific, technical and medical information products and services. The company works in partnership with the global science and health communities to publish more than 2,000 journals, including The Lancet and Cell, and close to 20,000 book titles, including major reference works from Mosby and Saunders. Elsevier’s online solutions include ScienceDirect, Scopus, Reaxys, ClinicalKey and Mosby’s Suite, which enhance the productivity of science and health professionals, and the SciVal suite and MEDai’s Pinpoint Review, which help research and health care institutions deliver better outcomes more cost-effectively.

A global business headquartered in Amsterdam, Elsevier employs 7,000 people worldwide. The company is part of Reed Elsevier Group plc, a world leading provider of professional information solutions. The group employs more than 30,000 people, including more than 15,000 in North America. Reed Elsevier Group plc is owned equally by two parent companies, Reed Elsevier PLC and Reed Elsevier NV. Their shares are traded on the London, Amsterdam and New York Stock Exchanges using the following ticker symbols: London: REL; Amsterdam: REN; New York: RUK and ENL.



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