Scientific Overview:

Research in the laboratory of Dr. Russell Taichman focuses on the role of osteoblasts in normal bone marrow function. The laboratory is currently trying to identify the osteoblast-derived factor(s) that support hematopoiesis. Identifying these mechanisms may someday ultimately reduce the morbidity/mortality associated with bone marrow transplants and will likely lead to the identification of novel methods to improve bone engraftment for regenerative therapies. Recent NIDCR grants have allowed the group to dissect the molecular events that mediate cell-to-cell adhesion between osteoblasts and hematopoietic stem cells. Part of the receptor complex that has been uncovered is novel and may be involved in how stem cells return to the marrow during bone marrow transplantation. In a second related project, the group is studying the mechanisms used by tumor cells to metastasize to the bone marrow. It has been found that part of the mechanism relates to products secreted by osteoblasts in the bone marrow that interact with receptors on tumor cells. Currently the focus is on the receptor CXCR4 (an HIV co-receptor). This receptor binds stromal derived factor-1 (SDF-1) which we believe directs the chemotaxis of prostate cancers towards the marrow. In fact, the group has recently demonstrated that blocking CXCR4 resulted in fewer tumors in animals. Recently funded projects include examinations of genetic variability in these genes that regulate tumor progression and metastasis.

Contact Information:

Russell S. Taichman D.M.D., D.M.Sc.                                                          Professor of Dentistry                                                                                Department of Periodontics and Oral Medicine                                               University of Michigan School of Dentistry
1011 North University Avenue.
Ann Arbor MI 48109-1078
Tel: (734) 764-1452.
Fax: (734) 763-5503
email: rtaich@umich.edu

Education
B.S.                                Villanova University (1983)
D.M.D.                             University of Pennsylvania (1986)
D.M.Sc.                           Harvard University (1990)
Certificate in Periodontics  Harvard University (1990)                                               Post-Doctoral Fellowship   University of Pennsylvania (1992)                             

                    
Biography

2005-Current Professor, Department of Periodontics and Oral Medicine
1998-2005 Associate Professor, Department of Periodontics, Prevention, &Geriatrics, University of Michigan School of Dentistry.                                                           
1998-Current Consultant; Dental Service, Ann Arbor VA Medical Center.                    1992-98 Assistant Professor, Department of Periodontics, Prevention & Geriatrics, University of Michigan School of Dentistry.
1991-92 Consultant, Dental Service, Philadelphia VA Medical Center.
1990-92 Postdoctoral Research Fellow, Department of Pathology & Laboratory Medicine, University of Pennsylvania School of Medicine.
1987-90 Orthopedic Research Fellow, Department of Orthopedics. Children's Hospital Corp. Boston, MA.
1986-87 Surgical Research Fellow, Department of Surgery, Brigham and Women's        Hospital, Boston MA.
1986-90 Fellow in Periodontology, Harvard University, School of Dental Medicine.

Research Interests

Project 1: Osteoblastic-Hematopoietic Interactions

The developmental mechanisms of bone and blood formation have traditionally been viewed as distinct, unrelated processes, but there is compelling evidence to suggest that they are functionally intertwined.  First, both cell populations originate in the bone marrow and come into direct physical contact with each other.  Indeed, in situ observations confirm that hematopoietic precursors reside in close proximity to endosteal surfaces in human bone marrow.  Moreover, in vitro studies demonstrate that tight adhesions between these cells are critical for long-term viability and development of primitive human hematopoietic cells.  Second, our in vitro experiments reveal that primary human osteoblasts (OBs) produce growth factors that may be essential for the survival, renewal and maturation of human hematopoietic stem cells (HSCs).  These important observations provide a glimpse of the potential dimensions and ramifications of HSC-OB interactions.  More research is required to secure a broader grasp of the cellular and molecular mechanisms that govern blood and bone biology.

We postulate that HSCs may be dependent on OBs for their survival in vivo and that HSCs influence OB behavior in intact animals.  We are currently in the process of trying to identify those osteoblast-derived factor(s) and the mechanisms that are used by osteoblasts to support hematopoiesis either through cell culture techniques or molecular/biochemical means.  Identifying the mechanisms used by osteoblasts to support hematopoiesis will ultimately reduce the morbidity/mortality associated with bone marrow transplantation for several of the bone marrow failure syndromes. These include, but not limited, the leukemia or any clinical condition requiring bone marrow transplantation.  The results will impact our understanding of the interactive biology of blood and bone cells in health and disease, lead to new strategies for the treatment of hematopoietic and osseous disorders and, one day this may be useful for gene therapy of hematopoietic disorders.

Project 2: Chemokines and Prostate Cancer Metastasis to Bone.

Prostate cancer is a common neoplasm and the second leading cause of cancer deaths in American males. Despite numerous advances, once the tumors metastasize, prostate cancer is almost invariably fatal.  The high mortality rate is principally due to the spread of malignant cells to many tissues including bone.  Because of these facts, there is a growing interest in the early detection and screening of men for prostate cancer, and for a greater understanding of the mechanisms that lead to metastasis. 

The development of metastasis is a complicated, multi-step process.  Briefly, malignant cells initially "escape" from the primary tumor, invade into surrounding tissues and enter into the vascular circulation.  If they are able to survive in the blood stream, they need to arrest at a secondary target site, cross the vascular barrier and migrate into the extravascular connective tissues.  Subsequently, the tumor cells must proliferate or grow, thereby establishing a secondary (or metastatic) tumor.  These events involve numerous cell-cell and cell-extracellular matrix adhesive interactions, which are mediated by many cell surface adhesion molecules. 

The metastasis of circulating prostate carcinoma cells is functionally akin to the behavior of blood cells which also home to bone marrow. There is now compelling evidence that suggests that stromal derived growth factor-1 or SDF-1 and its receptor CXCR4 play a pivotal role in blood cell homing to the marrow. As people working in bone biology often consider issues relating to bone metastasis, these recent findings have caused us to hypothesize that metastatic carcinomas utilized SDF-1 and CXCR4 to localize to bone. Our rationale being: if blood cells use this pathway, why should tumors develop a new pathway?

In our ongoing investigations we are focus on the fundamental mechanisms relating to the bone metastasis of prostate cancer.  We want to determine if prostate cancers express the CXCR4 receptors,  whether the expressed receptor is functional, and if we can limit the metastasis of prostate carcinomas to lodge and grow in the bone marrow using antibodies against CXCR4 and SDF-1.  We are confident that such observations are relevant to a more complete molecular understanding of the behavior of prostate cancer cells and that the new insights derived will lead to the development of innovative strategies to minimize the malignant spread of these cells to bone.

 

Publications (Selected)

Neiva K, Sun YX, Taichman RS. The role of osteoblasts in regulating hematopoietic stem cell activity and tumor metastasis. Braz J Med Biol Res. 2005 Oct;38(10):1449-54. Epub 2005 Sep 6. 

Koh AJ, Demiralp B, Neiva KG, Hooten J, Nohutcu RM, Shim H, Datta NS, Taichman RS, McCauley LK. Cells of the osteoclast lineage as mediators of the anabolic actions of parathyroid hormone in bone.
Endocrinology. 2005 Aug 4; [Epub ahead of print]

 Wang J, Wang J, Sun Y, Song W, Nor JE, Wang CY, Taichman RS.  Diverse signaling pathways through the SDF-1/CXCR4 chemokine axis in prostate cancer cell lines leads to altered patterns of cytokine secretion and angiogenesis.
Cell Signal. 2005 Dec;17(12):1578-92. 
 
Sun YX, Schneider A, Jung Y, Wang J, Dai J, Wang J, Cook K, Osman NI, Koh-Paige AJ, Shim H, Pienta KJ, Keller ET, McCauley LK, Taichman RS.  Skeletal localization and neutralization of the SDF-1(CXCL12)/CXCR4 axis blocks prostate cancer metastasis and growth in osseous sites in vivo.
J Bone Miner Res. 2005 Feb;20(2):318-29. 

Taichman RS. Blood and bone: two tissues whose fates are intertwined to create the hematopoietic stem-cell niche. Blood. 2005 Apr 1;105(7):2631-9. Epub 2004 Dec 7.

Loberg RD, Fridman Y, Pienta BA, Keller ET, McCauley LK, Taichman RS, Pienta KJ. Detection and isolation of circulating tumor cells in urologic cancers: a review.
Neoplasia. 2004 Jul-Aug;6(4):302-9.   

Liang Z, Wu T, Lou H, Yu X, Taichman RS, Lau SK, Nie S, Umbreit J, Shim H.
Inhibition of breast cancer metastasis by selective synthetic polypeptide against CXCR4. Cancer Res. 2004 Jun 15;64(12):4302-8.
 

Cooper CR, Sikes RA, Nicholson BE, Sun YX, Pienta KJ, Taichman RS.
Cancer cells homing to bone: the significance of chemotaxis and cell adhesion.
Cancer Treat Res. 2004;118:291-309. 

Crean SM, Meneski JP, Hullinger TG, Reilly MJ, DeBoever EH, Taichman RS.
N-linked sialyated sugar receptors support haematopoietic cell-osteoblast adhesions.
Br J Haematol. 2004 Feb;124(4):534-46. 

Dai J, Kitagawa Y, Zhang J, Yao Z, Mizokami A, Cheng S, Nor J, McCauley LK, Taichman RS, Keller ET. Vascular endothelial growth factor contributes to the prostate cancer-induced osteoblast differentiation mediated by bone morphogenetic protein.
Cancer Res. 2004 Feb 1;64(3):994-9. 

Sun YX, Wang J, Shelburne CE, Lopatin DE, Chinnaiyan AM, Rubin MA, Pienta KJ, Taichman RS. Related Articles, Expression of CXCR4 and CXCL12 (SDF-1) in human prostate cancers (PCa) in vivo.
J Cell Biochem. 2003 Jun 1;89(3):462-73.

Cooper CR, Chay CH, Gendernalik JD, Lee HL, Bhatia J, Taichman RS, McCauley LK, Keller ET, Pienta KJ.  Stromal factors involved in prostate carcinoma metastasis to bone. Cancer. 2003 Feb 1;97(3 Suppl):739-47. 

Keller ET, Zhang J, Cooper CR, Smith PC, McCauley LK, Pienta KJ, Taichman RS.
Prostate carcinoma skeletal metastases: cross-talk between tumor and bone.
Cancer Metastasis Rev. 2001;20(3-4):333-49. Review.

Petit I, Szyper-Kravitz M, Nagler A, Lahav M, Peled A, Habler L, Ponomaryov T, Taichman RS, Arenzana-Seisdedos F, Fujii N, Sandbank J, Zipori D, Lapidot T. G-CSF induces stem cell mobilization by decreasing bone marrow SDF-1 and up-regulating CXCR4. Nat Immunol. 2002 Jul;3(7):687-94. Epub 2002 Jun 17. Erratum in: Nat Immunol 2002 Aug;3(8):787. 
 

Taichman RS, Cooper C, Keller ET, Pienta KJ, Taichman NS, McCauley LK.
Use of the stromal cell-derived factor-1/CXCR4 pathway in prostate cancer metastasis to bone. Cancer Res. 2002 Mar 15;62(6):1832-7.

Taichman RS, Reilly MJ, Emerson SG. Related Articles, Links
The Hematopoietic Microenvironment: Osteoblasts and The Hematopoietic Microenvironment. Hematology. 2000;4(5):421-426.

Ponomaryov T, Peled A, Petit I, Taichman RS, Habler L, Sandbank J, Arenzana-Seisdedos F, Magerus A, Caruz A, Fujii N, Nagler A, Lahav M, Szyper-Kravitz M, Zipori D, Lapidot T.Induction of the chemokine stromal-derived factor-1 following DNA damage improves human stem cell function. J Clin Invest. 2000 Dec;106(11):1331-9. 

Eipers PG, Kale S, Taichman RS, Pipia GG, Swords NA, Mann KG, Long MW. Bone marrow accessory cells regulate human bone precursor cell development.
Exp Hematol. 2000 Jul;28(7):815-25. 

Hullinger TG, Taichman RS, Linseman DA, Somerman MJ. Related Articles, Links
Secretory products from PC-3 and MCF-7 tumor cell lines upregulate osteopontin in MC3T3-E1 cells. J Cell Biochem. 2000 Jun 12;78(4):607-16. 

Taichman RS, Reilly MJ, Matthews LS. Related Articles, Links
Human osteoblast-like cells and osteosarcoma cell lines synthesize macrophage inhibitory protein 1alpha in response to interleukin 1beta and tumour necrosis factor alpha stimulation in vitro. Br J Haematol. 2000 Feb;108(2):275-83. 

Takata T, D'Errico JA, Atkins KB, Berry JE, Strayhorn C, Taichman RS, Somerman MJ. Protein extracts of dentin affect proliferation and differentiation of osteoprogenitor cells in vitro. J Periodontol. 1998 Nov;69(11):1247-55.

Nassiri MR, Gilloteaux J, Taichman RS, Drach JC. Related Articles, Links
Ultrastructural aspects of cytomegalovirus-infected fibroblastic stromal cells of human bone marrow. Tissue Cell. 1998 Aug;30(4):398-406. 

 Taichman RS, Emerson SG. Related Articles, Links
The role of osteoblasts in the hematopoietic microenvironment.
Stem Cells. 1998;16(1):7-15.

Taichman RS, Reilly MJ, Emerson SG. Related Articles, Links
Human osteosarcomas inhibit hematopoietic colony formation: partial reversal by antibody to transforming growth factor-beta 1.
Bone. 1997 Oct;21(4):353-61.

Taichman RS, Nassiri MR, Reilly MJ, Ptak RG, Emerson SG, Drach JC. Infection and replication of human cytomegalovirus in bone marrow stromal cells: effects on the production of IL-6, MIP-1alpha, and TGF-beta1.
Bone Marrow Transplant. 1997 Mar;19(5):471-80.

Taichman RS, Reilly MJ, Verma RS, Emerson SG.                                       Augmented production of interleukin-6 by normal human osteoblasts in response to CD34+ hematopoietic bone marrow cells in vitro.
Blood. 1997 Feb 15;89(4):1165-72.  

Nassiri MR, Emerson SG, Devivar RV, Townsend LB, Drach JC, Taichman RS.  Comparison of of benzimidazole nucleosides and ganciclovir on the in vitro proliferation and colony formation of human bone marrow progenitor cells.
Br J Haematol. 1996 May;93(2):273-9. 

Taichman RS, Emerson SG. Related Articles, Links
Human osteosarcoma cell lines MG-63 and SaOS-2 produce G-CSF and GM-CSF: identification and partial characterization of cell-associated isoforms.
Exp Hematol. 1996 Mar;24(4):509-17.

Taichman RS, Reilly MJ, Emerson SG. Related Articles, Links
Human osteoblasts support human hematopoietic progenitor cells in vitro bone marrow cultures. Blood. 1996 Jan 15;87(2):518-24.

Taichman RS, Emerson SG.
Human osteoblasts support hematopoiesis through the production of granulocyte colony-stimulating factor.
J Exp Med. 1994 May 1;179(5):1677-82.

Taichman RS, Torigoe T, Reed JC. Related Articles, Links
A strategy for constructing inducible expression plasmids for T-lymphocytes.
Biotechniques. 1993 Feb;14(2):180-2.

Taichman RS, Hauschka PV. Related Articles, Links
Effects of interleukin-1 beta and tumor necrosis factor-alpha on osteoblastic expression of osteocalcin and mineralized extracellular matrix in vitro.
Inflammation. 1992 Dec;16(6):587-601.

Taichman RS, Torigoe T, Tanaka S, Miyashita T, Reed JC. Related Articles, Links
Gene transfer investigations of p56-LCK function in IL-2-dependent T-cell lines: implications for mechanisms of IL-2-signal transduction.
Cytokine. 1992 Nov;4(6):441-53.