The vast majority of solid tumors have a very low growth fraction at the time they become clinically evident, usually in the range of 3-7%. When the tumor is treated, the growth fraction increases in an effort to maintain the tumor cell mass. This is reminiscent of the organization of most organ systems. Resting bone marrow stem cells are recruited into cycle when under the influence of a myelotoxic stimulus. Surgical removal of a portion of the liver stimulates the recruitment of hepatocytes into the cell cycle to replace the removed tissue. Other examples could also be cited. What is of interest to us is how a tumor cell, with its many genetic abnormalities that tend to promote proliferation, is pulled out of the cell cycle in the first place. Some gene product that is working in the resting tumor cells has managed to antagonize all the oncogene mutations and missing or malfunctioning tumor suppressor gene products and stop the cell from dividing; and it does this reversibly. When the tumor perceives an attack that reduces its volume, cells can be recruited back into the cell cycle. We are separating fresh lymphoma specimens into dividing and nondividing populations, isolating total RNA, and using RAGEtag techniques, characterizing genes that are expressed in resting cells but not in dividing cells. Such messages will be isolated, their genes identified, and then the cDNA will be introduced into dividing cells to look for growth arrest.
