SENIOR SCIENTIST
Mary Helen Barcellos-Hoff, PhD

SCIENTISTS
Sylvain V. Costes, PhD
Philippe D. Gascard, PhD, DVM
Joni Mott, PhD

POSTDOCTORAL FELLOWS
Kumari Andarawewa, PhD
Arnaud Boissiere, PhD
Markus C. Fleisch, MD
Julia Kirshner, PhD
Christopher A. Maxwell, PhD
Hellen Oketch-Rabah, PhD
Olga Roman, PhD

RESEARCH STAFF
Shraddh Ravani
Sandhya Bhatnagar
Rosie Chau
William Chou
Berbi Chu
Jeremy Semeiks


GRADUATE STUDENTS
Rodrigo Fernandez-Gonzalez (Bioengineering)

UNDERGRADUATE STUDENTS
Claudia K. Kuper
Tyrone P. Chan
Tim Chi

ADMINISTRATIVE STAFF
Kat Wentworth

 

Cell function in complex three dimensional tissues is coordinated by soluble signaling peptides and by small molecules within the context of insoluble scaffolding provided by the extracellular matrix. Tissue interactions, mediated by the extracellular matrix and growth factors, can actively suppress malignant behavior by epithelial cells. Conversely, atypical interactions can become active participants in carcinogenesis. The dynamic interaction between target cells and the various cellular constituents of tissues is a novel target for therapeutics (Erickson and Barcellos-Hoff, 2003). Ionizing radiation (IR), a prototypic mutagen and carcinogen, as a consequence of medical, occupational and environmental exposure, rapidly and persistently alters tissue interactions (Barcellos-Hoff, Park and Wright, 2005). The challenge in predicting low dose/fluence radiation health effects in humans is to understand how cellular responses occurring in a multicellular context are integrated to produce an organismal response. Identifying when and how tissue alterations contribute to the action of IR as a carcinogen may provide a back door to inhibiting its carcinogenic potential, as well as a better understanding of how normal tissues suppress carcinogenesis.

Transforming growth factor 1ß (TGFß) is a prominent player in the response to IR, which in turn has revealed new aspects of its biology. An orchestrated multicellular response IR is important for rapid restoration of homeostasis and long-term prevention of cancer but it is unclear whether factors outside the cell influence DNA damage response. We have shown that TGF1, a pleiotropic cytokine, is essential for epithelial cells to mount the canonical DNA damage response (Ewan, 2002a). Irradiated Tgf1 null murine epithelial cells fail to undergo cell cycle arrest or apoptosis in response to irradiation in vivo. Recent cell culture experiments demonstrate that this response is restricted to epithelial cells and can be reversed by TGFß addition. A direct and specific requirement for TGF in the genotoxic stress program provides a vital link between cell fate and tissue integrity.

In normal mammary gland, TGF specifically inhibits the proliferative potential of mammary epithelial cells in response to ovarian steroids. TGF immunolocalization revealed striking epithelial heterogeneity during mammary stages characterized by proliferation (Ewan 2002b). Many cells downregulate TGF at estrus, consistent with its action as a growth inhibitor, but some mammary epithelial cells maintain prominent TGF1 activation. This observation suggested the possibility that TGF acts to restrain such cells from proliferating particularly in the presence of ovarian steroids. We found that TGF1-positive and steroid hormone receptor co-localize in an epithelial subpopulation and that TGF depletion specifically affects proliferation of hormone receptor positive cells (Ewan, 2005).

The laboratorys current focus is to study the multiple and complex mechanisms of regulation by TGF of epithelial function physiologically and in response to IR, and the consequences of its ultimate loss of function during carcinogenesis. The goal is to better understand how tissues integrate information across multiple scales of organization and to use this information in modeling critical events in carcinogenesis.

Mary Helen
Barcellos-Hoff

Senior Scientist/
Deputy Director,
Life Sciences Division

One Cyclotron Rd.
Mailstop: 977R225A
Berkeley, CA 94720
tel: (510)486-6371
fax: (510)486-4545
email: MHBarcellos-Hoff@lbl.gov

 

 

Publications

2005

Ewan, K.B., Oketch-Rabah, H.A., Ravani, S.A., Moses, H.L., Shyamala, G., and Barcellos-Hoff, M.H. (2005). Proliferation of adult estrogen receptor ax positive mammary epithelial cells is restrained by TGFß1. Am J Path 167, 409-417.

Barcellos-Hoff, M.H., Park, C.C., and Wright, E.G. (2005). Radiation and the microenvironment: Tumorigenesis and therapy. Nat Cancer Rev 5, 867-875.

Grimm, S.L., Contreras, A., Barcellos-Hoff, M.-H., and Rosen, J.M. (2005). Cell cycle defects contribute to a block in hormone-induced mammary gland proliferation in C/EBPbeta -null mice. J Biol Chem, M508167200.

Fernandez-Gonzalez, R., Barcellos-Hoff, M.H., and Ortiz de Solorzano, C. (2005). A tool for the quantitative spatial analysis of complex cellular systems. IIEEE Trans Image Process 14, 1300-1313.

Barcellos-Hoff, M.H., and Costes, S.V. (2005). A systems biology approach to multicellular and multi-generational radiation responses. Mutation Res In press.

Barcellos-Hoff, M.H. (2005). Redefining TGF-ß as a target in cancer. In Cancer Therapy: Molecular Targets in Tumour-Host Interactions, G. Weber, ed. (Horizon Press), pp. 63-81.

Barcellos-Hoff, M.H., and Medina, D. (2005). New highlights on stroma-epithelial interactions in breast cancer. Breast Cancer Res 7, 33-36.

Barcellos-Hoff, M.H. (2005). How tissues respond to damage at the cellular level. BJR Suppl. 27, 123-127.

2004

Muraoka-Cook, R.S., Kurokawa, H., Koh, Y., Forbes, J.T., Roebuck, L.R., Barcellos-Hoff, M.H., Moody, S.E., Chodosh, L.A., and Arteaga, C.L. (2004). Conditional overexpression of active transforming growth factor ß accelerates metastases of transgenic mammary tumors. Cancer Res 64, 9002-9011.

Fernandez-Gonzalez, R., Barcellos-Hoff, M.H., and Ortiz de Solorzano, C. (2004). Quantitative Image Analysis in Mammary Gland Biology. J Mammary Gland Biol Neoplasia 9, 343-359.

Barcellos-Hoff, M.H. (2004). Integrative radiation carcinogenesis: Interactions between cell and tissue responses to DNA damage. Sem Cancer Biol 15, 138-147.

2003

Park, C.C., Henshall-Powell, R., Erickson, A.C., Talhouk, R., Parvin, B., Bissell, M.J., and Barcellos-Hoff, M.H. (2003). Ionizing radiation induces heritable disruption of epithelial cell-microenvironment interactions. Proc Natl Acad Sci 100, 10728-10733.

Parvin, B., Yang, Q., Fontenay, G., and Barcellos-Hoff, M. (2003). BioSig: An imaging bioinformatics system for phenotypic studies. IEEE Transaction on System, Man, Cybernetric 33, 814-824.

Erickson, A.C., and Barcellos-Hoff, M.H. (2003). The not-so innocent bystander: Microenvironment as a target of cancer therapy. Expert Opin Ther Targets 7, 71-88.

2002

Ewan, K.B., Henshall-Powell, R.L., Ravani, S.A., Pajares, M.J., Arteaga, C., Warters, R., Akhurst, R.J., and Barcellos-Hoff, M.H. (2002a). Transforming Growth Factor-ß1 Mediates Cellular Response to DNA Damage in Situ. Cancer Res 62, 5627-5631.

Ewan, K.B., Shyamala, G., Ravani, S.A., Tang, Y., Akhurst, R.J., Wakefield, L., and Barcellos-Hoff, M.H. (2002b). Latent TGF-ß activation in mammary gland: Regulation by ovarian hormones affects ductal and alveolar proliferation. Am J Path 160, 2081-2093