eNews January 24, 2012

A better model of ovarian cancer

Ovarian cancer is the fifth most common cancer among women and causes more deaths per year than any other female reproductive cancer. It is difficult to detect until later stages, at which time it has usually metastasized widely (PubMed Health). Until now, no mouse satisfactorily modeled human ovarian cancer's growth, metastasis and tumor microenvironment. A research team led by Dr. Richard Bankert of the Department of Microbiology and Immunology, the State University of New York, University at Buffalo, and including Jackson Laboratory Professor Lenny Shultz, developed such a model in 2011. In a novel approach, this team demonstrated that the NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ or "NSG" mice (005557) can engraft human ovarian cancer cells and reproduce many aspects of the human cancer better than any previous model (Bankert et al. 2011). The model is helping researchers better understand, diagnose and design effective therapies for ovarian cancer.

"A key factor in the success of the engraftment and long-term survival of human tumor xenografts has been the use of the NSG mice. These mice have also been used most effectively to study the engraftment, growth and spontaneous metastasis of human tumor stem cells and have been shown to be significantly more efficient in the detection of tumorigenic cells. These severely immunodeficient mice will continue to be critical in establishing xenografts that recapitulate the growth and spreading patterns of tumors observed in patients and have the potential to serve as reliable preclinical models to evaluate cancer therapies" (Bankert et al. 2011).

NSG mice had previously been used to model human ovarian cancer. In that model, tumors grow from subcutaneously injected fresh solid human ovarian tumor fragments.  NSG mice support the original human tumor architecture and cell types for a long time without host-versus-graft (HVG) interference or host cell infiltration. However, it has two major shortcomings: the engrafted tumors do not grow and metastasize as they do in humans, and engraftment can be incomplete or variable.

To overcome these shortcomings, the Bankert team injected NSG mice orthotopically (intraperitoneally) with a suspension of human ovarian tumor-derived cell aggregates. These aggregates included tumor-associated lymphocytes and fibroblasts, which are thought to contribute to tumor growth and metastasis. This NSG model exhibits many features of human ovarian cancer:

  • Clinical signs of cancer are manifested over a prolonged period of time.
  • Tumors maintain a human architecture and microenvironment characterized by human CD45+, CD3+, CD20+, CD138+ leukocytes, fibroblasts and proliferating tumor cells.
  • Tumor ascites (excess abdominal fluid containing viable tumor cells) are produced during late cancer stages.
  • As cancer progresses, levels of serum and ascites CA125 (a relatively late-stage tumor marker) rise, just as they do in humans as cancer progresses, indicating that CA125 levels in this model could be used to monitor tumor progression and compound efficacy.
  • Tumors metastasize to numerous organs and tissues, including the bowel, omentum, diaphragm and lungs
  • The tumor microenvironment contains functional, tumor-associated T and B cells for prolonged periods, allowing researchers to study the roles of these cells and whether they can be manipulated to fight the tumors.

In summary, the Bankert team developed an NSG mouse model of ovarian cancer that recapitulates human tumor progression, metastasis, ascites formation and microenvironment better than any previous mouse model. The model is particularly useful for studying the functions of nonmalignant tumor-associated stromal cells, including fibroblasts, epithelial cells, and leukocytes, in tumor growth and metastases. A better understanding of these cells should greatly improve our ability to diagnose and treat human ovarian cancer.