Tumors, such as the murine Lewis lung carcinoma (LLC), produce granulocyte-macrophage colony-stimulating factor (GM-CSF), which increases the proportion 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. However, the possibility that the CD34(+) cells of tumor bearers might have enhanced survival abilities had not been considered. The present studies showed a significant baseline level of apoptotic cells in short-term (5-day) cultures of normal CD34(+) cells containing GM-CSF plus stem cell factor (SCF), and a markedly greater level of apoptosis in cytokine-deficient cultures. In contrast, CD34(+) cells from tumor bearers did not undergo such levels of apoptosis, even in the absence of cytokines. This resistance to apoptosis could be conferred to normal CD34(+) cells by culture with LLC-conditioned medium. Studies to elucidate possible mechanisms for the resistance to apoptosis by tumor-exposed CD34(+) cells showed increased levels of the pro-life gene product bcl-2. Finally, the resistance of tumor-exposed CD34(+) cells to ligation of the Fas receptor, a known apoptotic trigger in hematopoietic cells, was compared with that of control CD34(+) cultures. Whereas approximately half of the normal CD34(+) cells underwent apoptosis in response to Fas ligation, the tumor-exposed CD34(+) cells resisted apoptosis, even 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 of CD34(+) cells as previously thought, but also may be due to an increased resistance to apoptosis that is conferred by tumor-derived products and is associated with increased expression of bcl-2.
Copyright 1999 Wiley-Liss, Inc.