In the open plenary session on April 13th, Robert A. Weinberg from the Whitehead Institute for Biomedical Research discussed the mechanisms involved in metastasis in cancers. Weinberg noted that in vitro experiments conducted with epithelial cells from normal human breast tissues that had been transformed with transgenes encoding hTert and Ras cultivated in different culture media gave rise to two different subpopulations of tumor cells. One population of cells formed an adenocarcinoma which was highly metastatic while the other subpopulation produced cells that formed squamous cell carcinoma that was not metastatic. With additional experimental data, Weinberg deduced that the microenvironment drove the metastastic processes as a result of tumor-initiating stem cells having the ability to colonize and adapt to different tissue sites along with the important potential to self renew. In these secondary foci where the cancer stem cells had metastazied, Weinberg pointed out that the stroma contained infiltrating fibroblasts which caused the cancer cells to transition from epithelial to mesenchymal phenotype (EMT) as measured by the cells expressing a keratinocyte marker (cytokeratin+) converted to a mesenchymal phenotype (vimentin+). Experimental data further supported the concept that EMT conversion was the result of transcription factors such as Twist, FOXC2, and Snail, secreted into the microenvironment which caused pleiotropically reprogramming gene expression in epithelial cells to revert to a more primitive mesenchymal phenotype. Weinberg noted that the acquired phenotype was reversible. More importantly, experimental data supported the notion that "aggressive instigating tumors" secreted exocrine signals which perturb the bone marrow which subsequently gave rise to stromal precursors. These stromal progenitors were recruited to secondary tumor sites that supported the growth of the metastatic micro-colonies. Weinberg concluded that cancer and metastasis should be viewed globally as a systemic disease.

This week's post will be dedicated to the sessions, papers and posters presented at this year's AACR Annual Meeting held in San Diego, California. In April 14th's plenary session, Irving L. Weissman from Stanford University School of Medicine gave a lecture on hematopoietic stem cells (HSCs) and leukemia stem cells (LSCs). Weisman noted that in humans only the long-term HSCs with Flk2-,Thy-1low, c-kit+, and CD34- can self-renew, whereas the short-term HSCs (ST-HSCs) with Flk2+, Thy1+, CD34+, have a limited life span and can divide for about six weeks in vitro. Every cell division of the ST-HSCs takes them closer to their fate. In leukemia patients with acute myelogenous leukemia (AML), the leukemic stem cells are CD34+, CD38-, Thy1+, and Lin- formed normal colonies with the AML-1/ETO marker whereas, the multipotent progenitors (CD34+, CD38-, Thy1-, Lin-) formed leukemic blast colonies in vitro. Weisman suggested that the only a subset of self-renewing multipotent progenitors which can differentiate into different myeloid lineages can transfer the leukemia. Thus, the clonal progression in leukemia is at the level of stem cells, however, the progression to disease (blast crisis) is never at the level of stem cells and resides in self-renewing progenitors in which the Wnt signaling pathway is constantly on with active β-catenins accumulating in the nucleus. It also interesting to note that leukemic cells overexpress CD47 ("the don't eat me epitope"), which allow the cells to traffic through the reticulo-endolthelial system and avoid phagocytosis as the cells is trafficking through the blood. Similarly, normal HSCs in the bone marrow express low levels of CD47, and when it exits the niche and trafficks through the blood CD47 is upregulated.

In the the News and Views section of the April issue of Nature Medicine, Peter B. Dirks from the Univ. of Toronto observed that from from his analysis of the results of two studies examining (Joseph, N.M. et al. Cancer Cell [2008]13, 129-140 and Zheng, H. et al. Cancer Cell [2008]13, 117-128 2008) the cellular origins of a peripheral system tumors in mouse models of neurofibromatosis type 1 may reside in more differentiated progenitor cells than as a result of mutated stem cells. The results of the two previous study suggest that tumors in animal with a deficiency in the neurofibromin (Nf1) gene cancer arises from neural progenitor cells and not from neural crest stem cells during embryognesis and postnatal development. In the first study by Joseph et al. who examined prenatal development of mice with the Nf1 conditionally deleted in neural crest lineage cells at different stages of development, the investigators found that prenatal expansion of neural crest stem cells did not correlate with postnatal expansion. Thus, there may not be a direct link between stem cell activity and tumorigenesis. Additionally, the investigators found that Nf1 deficient embryonic neural crest cells did not give rise to tumors when they were transplanted into the nerves of adult mice. A second study by Zeng et al. demonstrated that Nf1 deletion in early embryonic neural crest stem cells gave rise to neurofibromas in the peripheral nerves, albeit in a delayed fashion. However, if the Nf1 gene was deleted later during embryonic development, tumors were not formed postnatally. Thus, tumors were formed only if genetic mutations occur early in the stem cell hierarchy. From these two published results, Dirks noted "that cancer researchers must continue to keep an open mind as they seek the cell of origin for cancers; not all fingers point to the cancer stem cell."

The phenomenon of epithelial to mesenchymal transition (EMT) in neoplasia has been correlated to a cancers becoming more aggressive and metastatic. It has been speculated that EMT involves activation of a rare subpopulation of cancer stem cells in the subpopulation of cells undergoing EMT that lead to metastasis. It also been reported that EMT facilitates the tissue remodeling of embryonic development. Australian scientists P. A. Gregory et al., from the Inst. of Med. and Vet. Science in Adelaide reported in the March 30th issue of Nature Cell Biology their findings on a class of microRNA-200 family were markedly downregulated in cells undergoing EMT. The suppression of miR-200a, miR-200b,miR-200c, miR-141 and miR-429 expression occurred in EMT cells responding to transforming growth factor beta (TGF-β). The investigators also noted that these five members of the microRNA-200 family cooperatively regulated the expression of the E-cadherin transcriptional repressors ZEB1 and SIP1. Thus, inhibition of the microRNAs resulted in an upregulation of ZEB1/SIP1 which leads to EMT. Conversely, upregulation of ecotopic microRNA expression in mesenchymal cells initiated mesenchymal to epithelial transition (MET). The authors concluded that "downregulation of microRNAs may be an important step in tumor progression." (It would be of interest to determine if these microRNA-200 have a role in the activation of quiescent cancer stem cells.)