JAX Notes April 01, 2009

JAX-engineered NSG mouse an innovative cancer research tool

The NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (005557) mouse, nicknamed "NSG" (for NOD scid gamma), is enabling cutting-edge HIV research (Kumar et al. 2008). In this issue, we call attention to the superior ability of this mouse to engraft human cells and tissues. As a result, new insights into the pathophysiology and development of therapies for several cancer types have been unveiled.

The NSG mouse is helping scientists solve many puzzling aspects of cancer.

NSG mouse has superior xenografting capability

In the last decade, several immunodeficient mouse strains have been constructed to facilitate the engraftment of foreign tissues and cells (Shultz et al. 2007). However, these strains maintain a residual immune system that mounts a substantial host-vs-graft innate immune response that may completely reject the xenograft.

In contrast, the NSG mouse, developed by JAX Professor Leonard D. Shultz, lacks mature T cells and B cells, and is deficient in several high-affinity receptors for cytokines (including IL2, IL4, IL7, IL9, IL15, and IL21) that block the development of NK cells and further impair innate immunity. Consequently, the NSG mouse engrafts human cells and tissues better than any other published mouse strain (Shultz et al. 2005).

Tumorigenic melanoma cells are common

The superior engrafting ability of the NSG mouse allowed a University of Michigan research team to partly answer a fundamental question in cancer biology: How common are human cancer stem cells, which have the ability to initiate new tumors? Previous studies in which human cancer cells were transplanted into NOD.CB17-Prkdcscid/SzJ (001303, commonly called NOD scid) and other strains of immunodeficient mice had indicated that these cells are rare, comprising no more than approximately 0.1% of all human cancer cells. These findings support the "cancer stem cell" model — that only a few tumor cells have autonomous tumorigenic potential.

However, the University of Michigan team found that approximately 25% to 27% of human melanoma cells transplanted in NSG mice are tumorigenic, suggesting that, at least in some cancers, cancer stem cells are more common than previously thought (Quintana et al. 2008).

CD19 expression defines tumorigenic B-ALL cells

Xenograft studies using the NSG mouse also helped clarify the nature of tumorigenic stem cells in primary human B-precursor acute lymphocytic leukemia (B-ALL), the most common type of childhood cancer. A European research team in collaboration with Professor Shultz transplanted cells from human B-ALL tumors into NSG mice and found that B cell precursors at different stages of maturation can engraft, initiate leukemia and continue to engraft and initiate leukemia in subsequent NSG mice over four serial transplantations spanning a 12-month period (leViseur et al. 2008). A second collaboration among Professor Shultz and Japanese and Chinese researchers showed that only the CD19-expressing cells can initiate B-ALL and have self-renewal capacity upon secondary transplantation (Kong et al. 2008). By shedding new light on B-ALL tumorigenesis, these results are helping researchers understand the mechanisms of chemotherapy resistance and may lead to the development of drugs that prevent B-ALL relapse or drug resistance.

Human lung cancer xenograft retains microenvironmental integrity

The NSG mouse's superior engrafting ability may yield new insights into another dreaded disease — lung cancer. Collaborating with Professor Shultz, researchers from State University of New York- (SUNY-) Buffalo found that non-disrupted pieces of human primary lung tumor transplanted into NSG mice can retain their cancerous architecture (including tumor-associated leukocytes, stromal fibroblasts and tumor cells) with limited host-vs-graft interference for up to nine weeks. Additionally, tumor-associated T cells from the spleens of xenografted mice can be maintained and expanded after adoptive transfer into tumor-free NSG mice. For the first time, a lung cancer model is providing scientists with an opportunity to study human tumor and tumor-stromal cell interactions in situ for prolonged periods (Simpson-Abelson et al. 2008).

These results of collaborative cancer research using the NSG mouse have significantly improved and will continue to be a valuable tool to understand human cancer. As Professor Shultz states, "Interdisciplinary collaboration among clinicians and basic researchers using the NSG mouse and other newly developed models holds great promise in accelerating our understanding of basic processes underlying cancer growth and resistance to treatment."

As an NCI-designated cancer center since 1983, JAX provides important resources to researchers, such as the NSG strain and is continually striving to fight against cancer through supporting investigator-initiated research.

References

Kong Y, et al. Leukemia 2008; 22:1207-13.
Kumar P, et al. Cell 2008; 134:577-86.
le Viseur C, et al. Cancer Cell 2008; 14:47-58.
Quintana E, et al. Nature 2008; 456:593-8.
Shultz LD, et al. Nat Rev Immunol 2007; 7:118-30.
Shultz LD, et al. J Immunol 2005; 174:6477-89.
Simpson-Abelson MR, et al. J Immunol 2008; 180:7009-18.