In the July 15th online edition of Nature Medicine, C. Dierks et al. from the Genomics Institute of the Novartis Research Foundation in San Diego, California reported the results of their study on how stromal cells from bone marrow and spleens of mice support leukemic cell survival. In the study, the investigators found that hedgehog ligands are secreted from bone-marrow, nodal, and splenic stromal cells as survival factors for malignant lymphoma and plasmacytoma from both mice and tumor tissues isolated from humans. By inhibiting the hedgehog pathway, the malignant cells were induced to undergo apoptosis through downregulation of Bcl-2. It was also found that hedgehog inhibition and apoptotic induction was independent of either the tumor suppressor p53 or Bmi1 expression. The researchers also found that in vivo inhibition of the hedgehog signaling pathway inhibited expansion of the lymphoma cells and reduced tumor mass in mice with the full blown disease. The investigators suggested that their data support the concept of hedgehog signaling as an important pathway for survival in B-cell and plasma-cell malignancies. The authors proposed that inhibition of the hedgehog pathway may provide new therapeutic strategies for treating lymphoma and multiple myeloma.

With a greater understanding of stem cell biology, scientists are now beginning to associate the relationship between oncogenes and the premise that these genes may also represent dysregulated stem cell genes. Thus, it was interesting to note that in the June 28th issue of Cell, T. Zou et al. from the University of Michigan reported findings that the forkhead/winged helix transcription factor, Foxp3, appears to also serve as a tumor suppressor gene in breast cancers. Foxp3 is also a marker for T regulatory cells as an important component for regulating the immune system. However, the investigators observed in heterozygous mice for the "scurfin" mutation of Foxp3 gene that the mice developed an unusually high rate of breast cancers. In these cancers, in which the wild type Foxp3 was inactivated, HER-2/ErbB2 was overexpressed. The experimental data further showed that Foxp3 bound and repressed the promoter for HER-2/ErbB2. In biopsy specimens of human breast cancers, downregulation of the Foxp3 resulted in significant overexpression of HER-2/ErbB2. The authors concluded that Foxp3 is an important regulator of HER-2/ErbB2 oncogene. (It would be of interest to determine if Foxp3 is involved in the regulatory pathway(s) for differentiating adult stem cells into mammary progenitor cells.)

In many solid tumors, the cancer consists of a heterogeneous population of malignant cells expressing epithelial markers. However, as the cancer progresses to a more aggressive state, the malignant cells appear more primitive with many expressing mesenchymal genes. Cancer biologists refer to this process as epithelial-mesenchymal transition (EMT) and cancer patients with such tumors have a poorer prognosis. In a paper by S. Shell et al., the scientists from Dartmouth Medical School noted in the June 28th online edition of PNAS, that "the early phases of carcinogenesis resemble embryonic development, often involving re-expression of embryonic mesenchymal genes." In a study involving a human tumor cell line, NC160, they found two "superclusters" of cells that express CD95 Type I and II cells (SC1 and SC2 cells, respectively). The researchers reported that the SC1 cells were less differentiated and expressed the mesenchymal markers while the SC2 cells had an epithelial gene signature. With miRNA expression analysis of the two cancer cell population, the investigators found that the transcription factor let-7 is less expressed in the SC1 cells. Since let-7 targets the high-mobility group A2 (HMGA2), the investigators proposed that let-7 and HMGA2 is a better predictor of prognosis than a classical marker such as E-cadherin, vimentin, and Snail. The authors concluded that their data supports observation of let-7 expression as a marker for less differentiated cancer.