Tips from the American Journal of Pathology

A group led by Dr. Massimo Loda at the Dana Farber Cancer Institute, Boston, MA has generated a preclinical model of human prostate cancer that mimics the genetic and growth behavior of primary tumors. Their report can be found in the April 2010 issue of the American Journal of Pathology.

Prostate cancer tends to develop in men over the age of 50 and is one of the most prevalent types of cancer in men. As prostate cancer is often slow-growing and symptom-free, treatment decisions are frequently based on a risk/benefit analysis determined by the underlying health and quality of life concerns of the patient.

Despite earlier detection and treatment of prostate cancer, novel biomarkers are needed to discriminate between aggressive and slow-developing tumors. Priolo et al therefore generated a preclinical model of human prostate cancer that mimics the genetic and growth behavior of primary tumors. In their model, the prostate cancer cells maintained both the histological and genetic characteristics of the parent tumor. In these mice, measurement of prostate-specific antigen levels correlated with tumor engraftment, but not engraftment of normal prostate tissue. Thus, this model should provide a platform for biomarker and drug discovery in prostate cancer.

Dr. Loda and colleagues conclude that "the mouse xenograft model that we have established through direct implantation of human primary prostate tumors represents a useful preclinical model for future applications in biological studies aimed at the identification of the most aggressive and possibly recurrent human localized prostate tumors as well as in biomarker discovery."

Priolo C, Agostini M, Vena N, Ligon AH, Fiorentino M, Shin E, Farsetti A, Pontecorvi A, Sicinska E, Loda M: Establishment and Genomic Characterization of Mouse Xenografts of Human Primary Prostate Tumors. Am J Pathol 2010, 176: 1901-1913

Dr. Adrian L. Harris and colleagues at the Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK have discovered that high expression levels of delta-like ligand 4 (DLL4) predict poor prognosis in breast cancer. They present these findings in the April 2010 issue of the American Journal of Pathology.

Survival of patients with breast cancer is dependent on cancer stage, aggressiveness, and genetic makeup. New diagnostic markers that predict prognosis would therefore aid in therapeutic decision-making.

DLL4, a cell-signalling molecule expressed on endothelial cells, is regulated by the therapeutic target VEGF (vascular endothelial growth factor) as well as by low oxygen levels, suggesting that it plays possible roles in new blood vessel formation and growth in tumors. To explore the role of DLL4 in breast cancer, Jubb et al examined breast adenocarcinomas, normal breast tissues, and angiosarcomas. They found that DLL4 was expressed in endothelial cells within the tumor proper of breast adenocarcinomas, but not in normal non-lactating breast tissue, and that high expression levels of DLL4 predicted poor prognosis regarding both overall and relapse-free survival. Assessing which patients express DLL4 may therefore may be used to predict patients' responsiveness to anti-VEGF therapies.

Dr. Harris and colleagues "suggest that tumor endothelial expression of Dll4 is a significant prognostic factor in early breast adenocarcinoma." They believe "these data may have clinical relevance, as preclinical models suggest that assessing which patients express Dll4 in their tumor endothelium may be critical in predicting benefit from anti-VEGF therapies."

Jubb AM, Soilleux EJ, Turley H, Steers G, Parker A, Low I, Blades J, Li J-L, Allen P, Leek R, Noguera-Troise I, Gatter KC, Thurston G, Harris AL: Expression of Vascular Notch Ligand Delta-like 4 (Dll4) and Inflammatory Markers in Breast Cancer. Am J Pathol 2010 176, 2019-2028

Researchers led by Dr. Parkash Gill of the University of Southern California, Los Angeles, CA have found that antibodies to EphB4 inhibit new blood vessel and tumor growth. They report their data in the April 2010 issue of the American Journal of Pathology.

Angiogenesis is the growth of new blood vessels from pre-existing vessels. It is critical in the progression and development of malignant tumors. The receptor tyrosine kinase EphB4, which is expressed in many epithelial cancers, plays a key role in angiogenesis.

Krasnoperov et al have developed two monoclonal antibodies against EphB4 that inhibit angiogenesis and tumor growth by two distinct mechanisms. MAb131 inhibits endothelial tube formation in vitro (a sign of angiogenesis) and tumor growth in vivo by inducing degradation of human EphB4. In contrast, although mAb147 does not degrade EphB4, it inhibits angiogenesis and tumor growth of both EphB4+ and EphB4- tumors, likely by modulating the vascular response. As humanized versions of both of these antibodies maintain these tumor-inhibitory functions, antibodies against EphB4 are strong candidates for clinical applications.

Dr. Gill's group "describe[s] novel EphB4-specific monoclonal antibodies that inhibit formation and maturation of newly forming vessels and inhibit tumor growth in vivo. … [They suggest that] antibodies targeting the EphB4 pathway, therefore, have the potential to inhibit tumor growth via multiple mechanisms."

Krasnoperov V, Kumar SR, Ley E, Li X, Scehnet J, Liu R, Zozulya S, Gil PS: Novel EphB4 Monoclonal antibodies modulate angiogenesis and inhibit tumor growth. Am J Pathol 2010, 176 2029-2038.

Dr. Roy L Silverstein and colleagues of the Cleveland Clinic, Cleveland, OH have identified HRGP as a new therapeutic target for anti-angiogenic cancer therapies. These results are presented in the April 2010 issue of the American Journal of Pathology.

Glioblastoma, which is the most common and aggressive form of brain tumor in humans, occurs in 2-3 per 100,000 people in the Europe and North America. Inhibiting angiogenesis, or new blood vessel growth, is a major therapeutic strategy for glioblastoma.

Interaction of CD36, a cell surface receptor expressed on the cells that line small blood vessels, with a secreted portion of brain angiogenesis inhibitor 1 (Vstat120) elicits an anti-angiogenic response. Klenotic et al discovered that Vstat120 binding to CD36 activated a pro-apoptotic (cell death-inducing) pathway, which could be blocked by HRGP through HRGP-Vstat120 binding. The HRGP-Vstat120 interaction restored endothelial cell migration and tube formation and increased brain tumor growth with corresponding increases in tumor blood vessel development. Indeed, HRGP expression levels were increased in human brain cancers, indicating that this angiogenic axis could provide a therapeutic target for anti-angiogenic cancer therapies.

The study by Klenotic et al suggests that "in conditions where neo-vasculature is poorly organized and "leaky", such as in tumor beds, or where platelet activation occurs, such as in a wound or inflammatory site, HRGP can accumulate in the extracellular matrix and abrogate the potent anti-angiogenic activity of a broad class of angiogenesis inhibitors."

Klenotic PA, Huang P, Palomo J, Kaur B, Van Meir EG, Vogelbaum MA, Febbraio M, Gladson CL, Silverstein RL: Histidine-rich Glycoprotein Modulates the Anti-angiogenic Effects of Vasculostatin. Am J Pathol 2010, 176: 2039-2050

For press copies of these articles, please contact Dr. Angela Colmone at 301-634-7953 or acolmone@asip.org.

The American Journal of Pathology, 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.