How Does Multistep Tumorigenesis Really Proceed?

Identifying the cancer cells-of-origin is of great interest, as it holds the potential to elucidate biologic mechanisms inherent in the normal cell state that have been co-opted to drive the oncogenic cell state. An emerging concept, proposed here, states that cancer stem cells, key players in cancer initiation and metastasis, arise when transit-amplifying cells with mutant genomes dedifferentiate and enter the stem cell state. This model contrasts with the notion that cancer stem cells are the direct products of neoplastically transformed normal tissue stem cells.National Institutes of Health (U.S.) (grant (P01 CA080111)National Institutes of Health (U.S.) (grant (R01 CA078461

Cancer Cell of Origin: Spotlight on Luminal Progenitors

Does basal type breast cancer arise from oncogenic transformation of a basal cell type? In this issue of Cell Stem Cell, Molyneux et al. (2010) investigate the provenance of the basal-type BRCA1 breast carcinoma and come up with unanticipated results

Asymmetric apportioning of aged mitochondria between daughter cells is required for stemness

By dividing asymmetrically, stem cells can generate two daughter cells with distinct fates. However, evidence is limited in mammalian systems for the selective apportioning of subcellular contents between daughters. We followed the fates of old and young organelles during the division of human mammary stemlike cells and found that such cells apportion aged mitochondria asymmetrically between daughter cells. Daughter cells that received fewer old mitochondria maintained stem cell traits. Inhibition of mitochondrial fission disrupted both the age-dependent subcellular localization and segregation of mitochondria and caused loss of stem cell properties in the progeny cells. Hence, mechanisms exist for mammalian stemlike cells to asymmetrically sort aged and young mitochondria, and these are important for maintaining stemness properties.National Science Foundation (U.S.). Long-Term Ecological Research Program (DEB-8811884)National Science Foundation (U.S.). Long-Term Ecological Research Program (DEB-9411972)National Science Foundation (U.S.). Long-Term Ecological Research Program (DEB-0080382)National Science Foundation (U.S.). Long-Term Ecological Research Program (DEB-0620652)National Science Foundation (U.S.). Long-Term Ecological Research Program (DEB-1234162)National Science Foundation (U.S.). (Biocomplexity Coupled Biogeocemhical Cycles. DEB-0322057)National Science Foundation (U.S.). Long-Term Research in Environmental Biology (DEB-0716587)National Science Foundation (U.S.). Long-Term Research in Environmental Biology (DEB-1242531)National Science Foundation (U.S.). Long-Term Research in Ecosystem Sciences (DEB-1120064)United States. Dept. of Energy. Program for Ecoysystem Research (DE-FG02-96ER62291)United States. Dept. of Energy. Office of Biological and Environmental Research. National Institute for Climatic Change Research (Grant DE-FC02-06ER64158

Integrin-β4 identifies cancer stem cell-enriched populations of partially mesenchymal carcinoma cells

Neoplastic cells within individual carcinomas often exhibit considerable phenotypic heterogeneity in their epithelial versus mesenchymal-like cell states. Because carcinoma cells with mesenchymal features are often more resistant to therapy and may serve as a source of relapse, we sought to determine whether such cells could be further stratified into functionally distinct subtypes. Indeed, we find that a basal epithelial marker, integrin- β4 (ITGB4), can be used to enable stratification of mesenchymallike triple-negative breast cancer (TNBC) cells that differ from one another in their relative tumorigenic abilities. Notably, we demonstrate that ITGB4 + cancer stem cell (CSC)-enriched mesenchymal cells reside in an intermediate epithelial/mesenchymal phenotypic state. Among patients with TNBC who received chemotherapy, elevated ITGB4 expression was associated with a worse 5-year probability of relapse-free survival.Mechanistically,we find that the ZEB1 (zinc finger E-box binding homeobox 1) transcription factor activity in highly mesenchymal SUM159 TNBC cells can repress expression of the epithelial transcription factor TAp63α (tumor protein 63 isoform 1), a protein that promotes ITGB4 expression. In addition, we demonstrate that ZEB1 and ITGB4 are important in modulating the histopathological phenotypes of tumors derived from mesenchymal TNBC cells. Hence, mesenchymal carcinoma cell populations are internally heterogeneous, and ITGB4 is a mechanistically driven prognostic biomarker that can be used to identify the more aggressive subtypes of mesenchymal carcinoma cells in TNBC. The ability to rapidly isolate and mechanistically interrogate the CSC-enriched, partially mesenchymal carcinoma cells should further enable identification of novel therapeutic opportunities to improve the prognosis for high-risk patients with TNBC

Asymmetric apportioning of aged mitochondria between daughter cells is required for stemness

By dividing asymmetrically, stem cells can generate two daughter cells with distinct fates. However, evidence is limited in mammalian systems for the selective apportioning of subcellular contents between daughters. We followed the fates of old and young organelles during the division of human mammary stemlike cells and found that such cells apportion aged mitochondria asymmetrically between daughter cells. Daughter cells that received fewer old mitochondria maintained stem cell traits. Inhibition of mitochondrial fission disrupted both the age-dependent subcellular localization and segregation of mitochondria and caused loss of stem cell properties in the progeny cells. Hence, mechanisms exist for mammalian stemlike cells to asymmetrically sort aged and young mitochondria, and these are important for maintaining stemness properties.Peer reviewe

The Complexities of Metastasis

International audienceTherapies that prevent metastatic dissemination and tumor growth in secondary organs are severely lacking. A better understanding of the mechanisms that drive metastasis will lead to improved therapies that increase patient survival. Within a tumor, cancer cells are equipped with different phenotypic and functional capacities that can impact their ability to complete the metastatic cascade. That phenotypic heterogeneity can be derived from a combination of factors, in which the genetic make-up, interaction with the environment, and ability of cells to adapt to evolving microenvironments and mechanical forces play a major role. In this review, we discuss the specific properties of those cancer cell subgroups and the mechanisms that confer or restrict their capacity to metastasize

PPARγ-independent induction of growth arrest and apoptosis in prostate and bladder carcinoma-0

<p><b>Copyright information:</b></p><p>Taken from "PPARγ-independent induction of growth arrest and apoptosis in prostate and bladder carcinoma"</p><p>BMC Cancer 2006;6():53-53.</p><p>Published online 6 Mar 2006</p><p>PMCID:PMC1450298.</p><p>Copyright © 2006 Chaffer et al; licensee BioMed Central Ltd.</p> ΔCT values were derived by normalisation to levels of the L32 housekeeping gene in each cDNA sample. * Significantly different to TSU-Pr1 (p < 0.001), significantly different to TSU-Pr1 and LNCaP, (p < 0.01), significantly different to DU145 (p < 0.03) (unpaired t test

PPARγ-independent induction of growth arrest and apoptosis in prostate and bladder carcinoma-2

<p><b>Copyright information:</b></p><p>Taken from "PPARγ-independent induction of growth arrest and apoptosis in prostate and bladder carcinoma"</p><p>BMC Cancer 2006;6():53-53.</p><p>Published online 6 Mar 2006</p><p>PMCID:PMC1450298.</p><p>Copyright © 2006 Chaffer et al; licensee BioMed Central Ltd.</p>), troglitazone (10 and 100 μM; TGZ), ciglitazone (40 μM; CGZ), rosiglitazone (10 μM; RGZ) and 15-deoxy-prostaglandin J2 (1 and 10 μM; 15dPGJ2) in the presence or absence of antagonist GW9662 (10 μM) at day 0. Values are mean ± SEM from Day 5. * All cell lines significantly different to the respective controls, TSU-Pr1 and TSU-Pr1-B2 significantly different to the respective controls (unpaired t test)