Stem cell and cancer biologists are currently investigating the microenvironment of the stem cell niche for its role in maintaining and determining the fate of both normal and cancer stem cells. A plethora of scientific data suggesting that cell-to-cell interaction, cell-to-tissue matrix contact, and the presence of certain factors and signaling molecules together within this stem cell niche/compartment regulate stem cell homeostasis. It now appears that the microenvironment provides the cues that instruct a stem cell to either self-renew or exit the niche and give rise to a subpopulation of progenitor cells.
Mina Bissell, Ph.D., of Lawrence Berkeley National Laboratory (www.lbl.gov), noted that in the context of the microenvironment and particularly the extracellular matrix, these extracellular elements have a profound influence on stem cell survival, proliferation, morphogenesis, differentiation, and cell fate.
From her earlier studies, Dr. Bissell found that the rous sarcoma virus, which causes tumors in chickens, when injected into chicken embryos does not induce tumor formation. On the other hand, if the infected embryonic cells are placed in a culture dish, there is massive transformation and subsequent tumor formation. These experiments provided proof that it is the microenvironment that drives phenotypic expression of oncogenes.
With mammary glands as the organ to study the microenvironment and its role in driving tissue structure and function, Dr. Bissell and her collaborators found that when the cells were grown in tissue cultures over a matrigel substrate, the dissociated cells reorganized and formed 3-D structures of mammary glands that were similar in function and size to the mammary glands in the body. They subsequently determined that an extracellular matrix (ECM) response element provides external signals that reorganize a cell’s chromatin and activates tissue specific genes.
Dr. Bissell also provided data demonstrating that if the breast cells are cultivated on a extracellular matrix deficient in lamin-1, the cells do not form acini-like structures, but instead create tumor-like 3-D structures. If myoepithelial cells are then added to the cell cultures, which are the only cells in the body known to produce lamin-1, the cells reorganize and form a normal acinus phenotype. Despite mutations in a cancer cell’s genome, Dr. Bissell provided data illustrating that breast cancer cells could also form normal acini if cultivated in an ECM containing lamin-1.
This organizational process to form either tumors or acini was reversible depending upon whether cancer cells were grown in a 2-D microenvironment (monolayer cultures) or in a 3-D microenvironment with ECMs. From these results, Dr. Bissell proposed that in the context of the microenvironment, “phenotype overrides genotype in normal mammary gland and breast cancer.”