American Association for Cancer Research

July 1 Cancer Research Highlights

PDF Version for Printing pdf4.gif

Selected Articles from the July 1, 2009 Issue

The articles referenced in this Highlights section will be available online in HTML and PDF formats to all interested users at no charge until the next issue of Cancer Research is published. Click on the article title to view the complete article.

View the Table of Contents for the July 1 issue of Cancer Research.


PDE11A and Testicular Germ Cell Tumors

Horvath et al.

Page 5301

The cause of testicular germ cell tumors (TGCT), one of the most common malignancies in men, remains elusive. Susceptibility to TGCT may best be explained by the combined interaction of multiple low-penetrance genetic variants. Recent findings implicated phosphodiesterase 11A (PDE11A), a molecule regulating cAMP levels, in endocrine tumors. Horvath and colleagues identified functional genetic variations in PDE11A to be more frequent among patients with bilateral or familial TGCT. The mutations reduced PDE11A activity and protein expression. Although the importance of cAMP signaling in regulating testicular function is well known, this is the first demonstration of any PDE involvement in TGCT. 
 

Notch1 Transforms Primary Melanocytes

Pinnix et al.

Page 5312

Pinnix et al.The molecular circuitry that results in malignant transformation of melanocytes thus far has been linked primarily to the MAPK pathway. Pinnix and colleagues present data demonstrating that Notch1 is highly activated in malignant melanoma and that inhibition of Notch1 suppresses growth of melanoma cells. Furthermore, introduction of an activated Notch1 transgene into primary human melanocytes conferred malignant properties to those cells, including anchorage-independent growth. The results suggest that Notch is an important etiological component of melanocytic transformation and that compounds targeting this pathway (i.e., γ-secretase inhibitors) represent a potential new class of drugs for patients afflicted with metastatic melanoma.


Wnt Signaling in Breast Cancer

DiMeo et al.

Page 5364

Metastasis is the major cause of morbidity and mortality in breast cancer patients. DiMeo and colleagues have developed a novel xenograft mouse model that develops spontaneous metastases in distant organs including the lungs and brain, and found that the lung metastases are enriched for genes in the wnt signaling pathway, which they show could classify human breast cancers of the basal subtype. Inhibition of the wnt pathway in human breast cancer cells reduced the capacity to self-renew and seed tumors in vivo and increased epithelial differentiation. These data provide evidence that human basal-like breast cancers exhibit increased wnt signaling activity and highlight the importance of the wnt pathway in regulating cancer cell differentiation, self-renewal, and progression. 


Roesli and colleagues used comparative proteomic analysis of two closely related murine teratocarcinoma cell lines with different metastatic potentials to reveal a dramatic increase in abundance at the cell membrane for a broad variety of proteins thought to reside in intracellular compartments. These finding were confirmed by immunofluorescence analysis of the corresponding cells and in syngeneic mouse liver metastasis models. Importantly, the accessibility of selected target proteins for intravenously administered antibodies was demonstrated by microautoradiographic analysis following intravenous administration. These results suggest that the expression of intracellular proteins on the membrane of metastatic cells is more common than previously thought. 


Virus-Associated Lymphoproliferative Disease

Lee et al.

Page 5481

Lee et al.Gammaherpesviruses such as Epstein-Barr virus are associated with malignancy in immune-suppressed individuals. Lee and colleagues report that infection of IFNγ-unresponsive mice with murine gammaherpesvirus 68 resulted in uniform development of angiocentric inflammatory lesions in the lung. Long-term outcomes of these lesions varied from spontaneous regression to pulmonary lymphoma. Both early and late stages were indistinguishable between wild-type and reactivation-defective virus infection, indicating that pathology depended on latent infection, but not on virus reactivation. Significantly, this mouse model of virus-associated pulmonary B-cell lymphoma closely mimics the full spectrum of human lymphomatoid granulomatosis, an Epstein-Barr virus–associated malignancy with no effective treatment.  


Liver Myeloid-Derived Suppressor Cells

Ilkovitch et al.

Page 5514

Myeloid-derived suppressor cells (MDSC) are a cell population that orchestrates immunosuppression in cancer and various other chronic pathologies. Ilkovitch and colleagues investigated homing and accumulation of MDSC in tumor-bearing mice and discovered that the liver is an organ to which MDSC home, accumulate, and expand, forming nests throughout the liver parenchyma. The authors also show that, in the liver, MDSC can interact with various immune cells such as Kupffer cells, and promote immunosuppression directly and indirectly.  


Top