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Malignant breast cancer cells to revert to normal with manipulation

19.04.2004


Speaking at Experimental Biology 2004, Dr. Mina Bissell describes research showing how manipulation of the extracellular matrix (a network of fibrous and globular proteins that surrounds breast cells) of non-malignant breast cells can lead to genomic instability via oxidative damage. She describes how manipulation of the microenvironment can allow malignant breast cancer cells to revert to normal cells again. She also describes how the tissue culture of the extracellular matrix affects the cancerous cells’ resistance to chemotherapy, independently of the characteristics of the malignancy itself.



Her presentation is part of the scientific program of the American Association of Anatomists, one of the six sponsoring societies of this year’s Experimental Biology meeting.

Dr. Bissell, a Distinguished Scientist at the Lawrence Berkeley Laboratory, is best known as the researcher who uncovered the critical role of extracellular matrix (ECM) in normal breast function and how its aberration may contribute to breast cancer development. While the role of ECM during embryonic development had been recognized for decades, its important role in tissue-specific function was not appreciated before the work in a handful of laboratories including Dr. Bissell’s laboratory. In fact, ECM was regarded as scaffolding for tissues and not much more.


Dr. Bissell postulated in 1981, and later showed experimentally, that the ECM was part of a "dynamic reciprocity" in the social interaction between cells and the nucleus much like hormones and growth factors, with the ECM at times telling the nucleus of the cells what to do and thus directing gene expression in conjunction with these other factors. She had chosen the breast to study the critical role of the ECM in normal breast tissue, a model she had selected because it continues to change throughout life of women in puberty, pregnancy, lactation, and once breast feeding is done (involution). In some of their earliest work, Dr. Bissell and her collaborators reported when breasts cells were placed on Petri dish tissue culture (2-D environment), even with all the right hormones and nutrients, they grew but did not differentiate and behave as breast cells do in the body. But when they were embedded in a 3-D extracellular matrix that mimicked real, living tissues, then the cells came together and organized as they would in the body, making tissue-like structures.

Studying how cancers develop and spread was a natural next step. One of the 3-D cell pioneers, Dr. Bissell believes science has concentrated too much on the cancer cell itself, when at times it’s what is outside those cells that lead to the affected cell’s genomic instability and mutation. Otherwise, she asks, why does everyone who has a BRCA 1 or 2 mutations not get breast cancer in every cell of the breast or ovary or indeed get it at all? Or perhaps more interestingly, since women who do have the mutation have it in every cell of their body, why does it only cause breast cancer and/or ovarian cancer? Why not also cancer of the skin or gut?

The 20th century will be remembered for the discovery of how genetic defects contribute to cancer. But in the 21st century, increasing evidence is being placed on the cellular microenvironment that makes up the context of cancer, both in ontogenesis, signaling the cell to permit expression of a cancer-causing gene, and in metastasis, when the nature of the ECM and its degrading enzymes may help allow cells to exist in microenvironments that differ from those in which they originated. Dr. Bissell’s research into the sophisticated manner in which the cellular environment affects gene expression within breast cells supports her belief that both normal and malignant cells are plastic and malleable, that normal cells can become malignant if the microenvironment is adversely affected, and that cancer cells even with many mutations can still become reverted to a normal phenotype. She also believes that the architecture of the tissue is important in how a tissue behaves and how it responds to chemotherapeutic agents.

Sarah Goodwin | EurekAlert!
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