Increased resistance to apoptosis by bone marrow CD34(+) progenitor cells from tumor-bearing mice

Tumors, such as the murine Lewis lung carcinoma (LLC), produce granulocyte- macrophage colony-stimulating factor (GM-CSF), which increases the proporti on of CD34(+) hematopoietic progenitor cells in the bone marrow and in the periphery. This increase in peripheral CD34(+) cells had been attributed to the growth-promoting and mobilizing effects of the tumor-derived GM-CSF. H owever, the possibility that the CD34(+) cells of tumor bearers might have enhanced survival abilities had not been considered. The present studies sh owed a significant baseline level of apoptotic cells in short-term (5-day) cultures of normal CD34(+) cells containing GM-CSF plus stem cell factor (S CF), and a markedly greater level of apoptosis in cytokine-deficient cultur es. In contrast, CD34(+) cells from tumor bearers did not undergo such leve ls of apoptosis, even in the absence of cytokines. This resistance to apopt osis could be conferred to normal CD34(+) cells by culture with LLC-conditi oned medium. Studies to elucidate possible mechanisms for the resistance to apoptosis by tumor-exposed CD34(+) cells showed increased levels of the pr o-life gene product bcl-2. Finally, the resistance of tumor-exposed CD34(+) cells to ligation of the Fas receptor, a known apoptotic trigger in hemato poietic cells, was compared with that of control CD34(+) cultures. Whereas approximately half of the normal CD34(+) cells underwent apoptosis in respo nse to Fas ligation, the tumor-exposed CD34(+) cells resisted apoptosis, ev en though their surface Fas expression was greater than that of normal CD34 (+) cells. Thus, our results show that the increased level of CD34(+) cells in tumor bearers is due not only to an increased growth and mobilization o f CD34+ cells as previously thought, but also may be due to an increased re sistance to apoptosis that is conferred by tumor-derived products and is as sociated with increased expression of bcl-2. (C) 1999 Wiley-Liss, Inc.