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 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.
Research Service, Hines Veterans Affairs Hospital, Hines, IL, USA.
M R
MR
Young
M A
MA
Wright
D M
DM
Lathers
K A
KA
Messingham
D000818:Animals; D018952:Antigens, CD34; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D015415:Biomarkers; D018827:Carcinoma, Lewis Lung / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009363:Neoplasm Proteins / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D019089:Stem Cell Factor / Q000494:pharmacology; D015854:Up-Regulation
D018952:Antigens, CD34; D015415:Biomarkers; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D019089:Stem Cell Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor