Martin Haas
e-mail: mhaas@ucsd.edu
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My group is active in two fields, (i) the isolation and characterization of stem cells from the human amniotic fluid as a source of human stem cells and (ii) the role of cancer stem and progenitor cells in prostate cancer.
(i). Does the amniotic fluid contain cells with stem cell characteristics? Can amniotic fluid-derived stem cells be grown and maintained in non-differentiated state in culture? Do they differentiate into functional cell types? If stem cells can be found in the human amniotic fluid, can these be used in future regenerative medical procedures? Unlike the isolation of human embryo stem cells from in vitro-fertilized blastocysts, amniocentesis is a non-controversial procedure that has been practiced for >25 years, and has been found to be medically safe.
Indeed, amniotic fluid at all gestation times contains stem-like cells. Multipotent Amniotic Fluid/Em-bryonic Stem Cells [MAFSC cells] have been grown from amniotic fluid of 16-week pregnancies and up to and including term pregnancies. MAFSC cells can be grown in culture using highly specific growth conditions and can be differentiated into five different directions. MAFSC cells resemble human Adult Stem Cells [ASC] and, like ASCs they are mortal, i.e. they undergo senescence, and are not tumorigenic in vivo like hES cells. Non-genetic methods are being pursued to maintain the self-renewal of MAFSC cells for long periods while preventing senescence, even as their conversion into cancer cells is precluded. MAFSC cells growing in suspension can be maintained in vitro for an apparent infinite time. MAFSC suspension stem cells differentiate into a rapidly-proliferating, adherent progenitor population that is capable of multipotent differentiation. Hence, our MAFSC stem cell system appears to be ready for its exploitation in potential regenerative medicine approaches.
One aim of our work is the study of amniotic fluid-derived stem cells as initiators of organogenesis in response to the combined effects of chemical, physical, and environmental cues.
(ii). In the light of major advances in our knowledge of oncogenes, tumor suppressor genes, cell signaling and genetic instability, the relative dearth of success in the treatment of many recurring human cancers is distressing. There appears to be a systematic error in our approach to human cancer, resulting in the discrepancy between our grasp of the carcinogenic process and actual cancer treatment.
The early steps in the genesis of human cancer are more closely associated with the inhibition of cell differentiation than with the activation of oncogenes or the loss of tumor suppressor or apoptosis gene function. In other words, cancer is a primarily a disease of cell differentiation. More than 80% of human cancers are of epithelial origin and the stromal cells that surround and sustain epithelia affect their development in a tightly controlled fashion. Stroma-controlled differentiation of epithelia is subject to the controls of five broadly active intercellular signaling pathways. Disruption of any of these pathways may initiate the development of epithelial tumor cells through the abrogation of epithelial cell differentiation and the acquisition of carcinogenic potential. Alterations in other genes may follow the abrogation of differentiation and these alterations may not be the proximal cause of carcinogenesis. We hypothesize that most cancers originate in epithelial stem/progenitor cells, not in differentiated cells. The great majority of differentiated tumor cells that make up a cancer are the wrong cells to be targeted in cancer treatment. Rather, Cancer Stem Cells should be isolated and studied, and Cancer Stem Cell-specific markers sought and targeted.
To answer this challenge, we study the characteristics of stem cells grown from surgical samples of prostate cancer and normal prostate tissue, their modes of self-renewal and differentiation. Using different growth conditions, four different cell types have routinely been grown from prostate tissue, whether normal or cancerous. Prostate (i) stem cells, (ii) transit/amplifying = progenitor cells, (iii) neuroendocrine cells and (iv) stromal fibroblasts. One characteristic common to all four prostate cell types – whether from normal or malignant prostate tissue – is the surprising finding that they all are mortal and are subject to the induction of senescence. Thus, the great majority of prostate local tumor cells are of a pre-malignant phenotype, not of malignant characteristics as histo/pathological data may suggest. Indeed, the natural history of prostate carcinomagenesis suggests that the local tumors are pre-malignant unless…… metastasis sets in.
The mechanism of induction of the metastatic phenotype in local prostate carcinoma cells is not known. Nor is it sufficiently known what novel antigens are displayed during metastatic conversion, what genes are associated with such conversion, or how many different mechanisms may result in metastatic conversion. We hypothesize that malignant conversion of prostatic pre-carcinoma cells is associated with the acquisition of immortality and the loss of the mortal/senescent phenotype. Having developed a complete complement of prostate cells in vitro, we study metastatic conversion of pre-malignant human prostate cells in vitro seeking to determine what genes and markers associated with this (rare) event. The purpose of the exercise is the identification of markers valuable in the diagnosis, staging, prognosis, and targeting of metastatic prostate cancers.
One attractive aspect of the propagation of four different classes of cells from normal and carcinoma prostate tissue is our ability to differentiate prostate stem cells into all the known cells of the organ. Thus, we can follow the generation of a “prostate” – or its different differentiating cell types – in two-dimensional cell cultures. Using prostate stem cells, a three dimensional “prostate” will be generated in the future.[1]. Barria, E., Mikels, A., and Haas, M. (2004) Maintenance and Self-Renewal of Long-Term Reconstituting Hematopoietic Stem Cells Supported by Amniotic Fluid. Stem Cells and Development. Oct;13 (5):548-562..
[2]. Barria, E., Blankevoort V, and Haas, M. (2004). Downstream Effectors of the bHLH Protein HES1. Submitted.
Martin Haas received his BS degree in Electrical Engineering from the Technion, Israel Institute of Technology and his Ph.D. in Biophysics from the University of California, Berkeley. During his post-doctoral research at the Salk Institute, he worked on the DNA tumor viruses under the direction of Drs. Renato Dulbecco and Marguerite Vogt. As Senior Scientist at the Weizmann Institute and then as Professor at UCSD, Dr. Haas has studied radiation-induced leukemia in mice, the Radiation Leukemia Virus, followed by work in the oncogene and the tumor suppressor fields. Based on his extensive experience in the areas of virology, cell biology and the use of gene transfer vectors, Dr. Haas recently entered the fields of stem cell research.
