Kohrt, H. E., Houot, R., Weiskopf, K., Goldstein, M., Lund, P., Scheeren, F., Czerwinski, D., Colevas, A. D., Weng, W., Clarke, M. F., Carlson, R. W., Sunwoo, J., Tedder, T., Chen, L., Levy, R. The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Patsialou, A., Bravo-Cordero, J., Wang, Y., Liu, H., Clarke, M. F., Condeells, J. S. Deregulation of stem cell self-renewal pathways in cancer, MicroRNA-30c inhibits human breast tumour chemotherapy resistance by regulating TWF1 and IL-11. Liu, H., Bockhorn, J., Dalton, R., Chang, Y., Qian, D., Zitzow, L. A., Clarke, M. F., Greene, G. L. Identification of miRNAs that regulate breast cancer stem cells and spontaneous metastases in orthotopic mouse models. Sikandar, S. S., Kuo, A. H., Kalisky, T. n., Cai, S. n., Zabala, M. n., Hsieh, R. W., Lobo, N. A., Scheeren, F. A., Sim, S. n., Qian, D. n., Dirbas, F. M., Somlo, G. n., Quake, S. R., Clarke, M. F. Control of inflammation by stromal Hedgehog pathway activation restrains colitis. Cancers originally develop from normal cells that gain the ability to proliferate aberrantly and eventually turn malignant. Using terminal transferase-mediated dUTP-digoxigenin nick end labeling, we observed apoptotic cells at sites of bcl-xs adenoviral injection. In Down's Syndrome (DS), triplication of Usp16 dampens the activation of the Wnt pathway. We report that Bcl-XL, which functions like Bcl-2 to inhibit apoptosis, is highly expressed in MCF-7 human breast carcinoma cells. In contrast, AdEHE2F was attenuated in nontransformed quiescent cells growing under normoxic conditions, suggesting that an intact pRB pathway with low levels of E2F transcription factors acts as a negative modulator for the virus. Profiles. We developed an immunodeficient mouse model to test the tumorigenic potential of different populations of cancer cells derived from primary, unmanipulated human HNSCC samples. Advances in our understanding of apoptosis has identified the Bcl-2 family as a mediator of most apoptosis pathways, including those initiated by oncogenes, tumor suppressor genes, growth factor withdrawal, and external damaging signals. Under these conditions, the cultures produced as many cells as were inoculated every 2 weeks and led to a greater than 2.5-fold expansion in terms of the number of nonadherent cells produced over a 6- to 8-week period. Four major epithelial subtypes or transcriptional states were revealed by gene expression analysis of selected populations of single cells. These results suggest that LEFTY1 is an endogenous dual-SMAD inhibitor and that suppressing its function may represent a therapeutic vulnerability in breast cancer. MMTV-Wnt-1 breast tumors were harvested, dissociated into single-cell suspensions, and sorted by flow cytometry on Thy1, CD24, and CD45. A., Patsialou, A., Qian, D., Lin, J., Wen, S., Chang, Y., Bachmann, M. H., Shimono, Y., Dalerba, P., Adorno, M., Lobo, N., Bueno, J., Dirbas, F. M., Goswami, S., Somlo, G., Condeelis, J., Contag, C. H., Gambhir, S. S., Clarke, M. F. Rothenberg, M. E., Clarke, M. F., Diehn, M. DLL4 Blockade Inhibits Tumor Growth and Reduces Tumor-Initiating Cell Frequency. Professor William Clarke. We proposed that epithelial tissue stem cells and their cancer stem cell (CSC) counterparts may also share this property. CD47 is a ligand for SIRP, a protein expressed on macrophages and dendritic cells. The successful ex vivo reconstruction of human bone marrow is an extraordinarily important basic scientific and clinical goal. View details for Web of Science ID 000345638500001, View details for DOI 10.1158/1538-7445.AM2014-SY12-04, View details for Web of Science ID 000349910205454, View details for Web of Science ID 000351670400001. View details for DOI 10.1073/pnas.1121623109, View details for DOI 10.1158/1538-7445.AM2012-3331, View details for Web of Science ID 000209701505088, View details for DOI 10.1158/1538-7445.AM2012-1012, View details for Web of Science ID 000209701505194. Patsialou, A., Bravo-Cordero, J. J., Wang, Y., Entenberg, D., Liu, H., Clarke, M., Condeelis, J. S. Intravital multiphoton imaging reveals multicellular streaming as a crucial component of in vivo cell migration in human breast tumors. Disclosure of potential conflicts of interest is found at the end of this article. It is unusual among haemopoietic cell lines in that one of these is c-sis, the gene from which the oncogene v-sis of the simian sarcoma virus was derived, and perhaps the gene for platelet-derived growth factor (PDGF). G418-resistant clones, which expressed the c-sis cDNA, were selected and characterized. Using this system, we have generated AdEHT2 and AdEHE2F, two conditionally replicative adenoviruses for the treatment of breast cancer. Here, a systematic approach using bioinformatics and array hybridization techniques to analyze gene expression profiles in HSCs is described. Breast cancers contain a minority population of cancer cells characterized by CD44 expression but low or undetectable levels of CD24 (CD44+CD24-/low) that have higher tumorigenic capacity than other subtypes of cancer cells.We compared the gene-expression profile of CD44+CD24-/low tumorigenic breast-cancer cells with that of normal breast epithelium. In several forms of human cancer, only a phenotypic subset of cancer cells, usually termed "cancer stem cells" (CSC), can initiate tumor growth when transplanted. Cancers arise in a tissue as the culmination of a series of mutations that activate oncogenes and inactivate tumor suppressor genes. Lee, J. J., Rothenberg, M. E., Seeley, E. S., Zimdahl, B., Kawano, S., Lu, W., Shin, K., Sakata-Kato, T., Chen, J. K., Diehn, M., Clarke, M. F., Beachy, P. A. Increased levels of Bcl-XL were found in a subset of primary human breast carcinomas, as well as in the breast cancer line, T47D. In combination with geometric and dynamic approaches to reconstructing physiological bone marrow microenvironments, we believe that this approach has promise for reconstructing human bone marrow ex vivo, thereby permitting its application to a variety of basic and clinical problems. Bmi1 is required for the maintenance of adult stem cells in some tissues partly because it represses genes that induce cellular senescence and cell death. We examined the effect of lower levels of c-sis expression on the phenotype of NIH 3T3 fibroblasts. Usp16 regulation of the Wnt pathway in mouse and human tissues is at least in part mediated by activation of Cdkn2a, a regulator of senescence. This effect was associated with a loss of the G1 specificity of p53-mediated cell cycle arrest. We developed a new technique that replaces immunoprecipitation with a simplified chromatin fragmentation and proximity ligation step that eliminates bead purification and washing steps. Tumor kinetic rate constants (K1, k2, k3) and net rate of FDG phosphorylation (K = [K1.k3]/[k2 + k3]) in tumors were calculated from the dynamic data by means of a three-compartment model, assuming k4 = 0.Viable tumors (n = 10) showed intense FDG uptake and could easily be differentiated visually from mature teratoma (n = 6) and necrosis or scar (n = 10). Our metastatic cancer models, combined with noninvasive imaging techniques, constitute an integrated approach that could be applied to dissect the molecular mechanisms underlying the dissemination of metastatic CSCs (MCSCs) and to explore therapeutic strategies targeting MCSCs in general or to evaluate individual patient tumor cells and predict response to therapy. View details for Web of Science ID A1995TE58500016. The amine-derivatized biotinylated GM-CSF analogues retained biological activity, could specifically label cell surface receptors, and may be useful nonradioactive probes with which to study GM-CSF receptor cytochemistry and receptor modulation by flow cytometry. His course "Justice" is the first Harvard course to be made freely available online and on television. Emerson, S. G., Palsson, B. O., Clarke, M. F., Silver, S. M., Adams, P. T., Koller, M. R., Van Zant, G., Rummel, S., Armstrong, R. D., MALUTA, J. Estrogen response elements and hypoxia-responsive elements were combined to activate transcription in cells that present at least one of these characteristics. Rachel Ellehuus. Recent evidence suggests that a subset of cancer cells within some tumors, the so-called cancer stem cells, may drive the growth and metastasis of these tumors. Moreover, the inherent ability of residual CoCSC to generate tumors appears preserved. Prince, M. E., Sivanandan, R., Kaczorowski, A., Wolf, G. T., Kaplan, M. J., Dalerba, P., Weissman, I. L., Clarke, M. F., Ailles, L. E. Chromosome 5q deletion and epigenetic suppression of the gene encoding alpha-catenin (CTNNA1) in myeloid cell transformation. Stromal Gli2 activity coordinates a niche signaling program for mammary epithelial stem cells. Park, I., Qian, D., Kiel, M., Becker, M., Prohaska, S., Weissman, I., Morrison, S., Clarke, M. Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. The AKR/J chromosome 17 locus was not sufficient to increase HSC frequencies when bred onto a C57BL background. View details for DOI 10.1073/pnas.0703478104, View details for Web of Science ID 000247363000044, View details for PubMedCentralID PMC1891215. Liu, R., Wang, X., Chen, G. Y., Dalerba, P., Gurney, A., Hoey, T., Sherlock, G., Lewicki, J., Shedden, K., Clarke, M. F. Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Within 24-48 hr, viral RNA expression increased at least four- to eightfold. We found 37 microRNAs that were differentially expressed between human BCSCs and nontumorigenic cancer cells. By immunohistochemical analysis, the CD44(+) cells in the tumor express high levels of nuclear BMI1, and are arrayed in characteristic tumor microdomains. Although many tumor cell lines undergo apoptosis when p53 is expressed, the T47D transfectants remained viable at temperatures permitting wild-type p53 phenotype. Here, we show that LEFTY1, a secreted inhibitor of NODAL/SMAD2 signaling, is produced by mammary progenitor cells and, concomitantly, suppresses SMAD2 and SMAD5 signaling to promote long-term proliferation of normal and malignant mammary epithelial cells. Sen, A., Rothenberg, M. E., Mukherjee, G., Feng, N., Kalisky, T., Nair, N., Johnstone, I. M., Clarke, M. F., Greenberg, H. B. Remodeling of Endogenous Mammary Epithelium by Breast Cancer Stem Cells. Finally, the laboratory is actively pursuing how cancer stem cells self-renew to maintain themselves and escape the genetic constraints on unlimited self-renewal that regulate normal stem cell numbers. Conclusions Lack of CDX2 expression identified a subgroup of patients with high-risk stage II colon cancer who appeared to benefit from adjuvant chemotherapy. In contrast, C5-bGM-CSF binding above background fluorescence could not be detected using this system, suggesting that this derivative could bind to and activate the receptor, but not simultaneously bind fluorescein-conjugated avidin. van Weele, L. J., Scheeren, F. A., Cai, S. n., Kuo, A. H., Qian, D. n., Ho, W. H., Clarke, M. F. Single-cell transcriptional diversity is a hallmark of developmental potential. Professor Michael Clarke said that sending soldiers to take Kyiv was 'massively foolish' and could become a 'peak Putin' moment that leads eventually to his downfall. Breast cancer is the most common malignancy in United States women, accounting for >40,000 deaths each year. View details for Web of Science ID A1988L925300043. Microarray-based multigene-expression signatures derived from stem cells and progenitor cells hold promise, but they are difficult to use in clinical practice. A full-length human c-myb cDNA clone has been isolated from a CCRF-CEM leukemia cell cDNA library. Through this property, striking parallels can be found between stem cells and cancer cells: tumours may often originate from the transformation of normal stem cells, similar signalling pathways may regulate self-renewal in stem cells and cancer cells, and cancer cells may include 'cancer stem cells' - rare cells with indefinite potential for self-renewal that drive tumorigenesis. This report summarizes the major topics discussed and the future directions that research should take. That signaling pathways such as Bmi1 and Wnt have similar effects in normal and cancer stem cell self-renewal suggests that common molecular pathways regulate both populations. Comparing the expression signature of normal HSC to that of LSC, we identified 3,005 differentially expressed genes. Results The transcription factor CDX2 ranked first in our screening test. Course to be made freely available online and on television derived from stem cells and progenitor cells promise. 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