Tumor dormancy and cell signaling. V. Regrowth of the BCL1 tumor after dormancy is established.
The majority of BALB/c mice immunized with the BCL1 lymphoma-derived idiotype (Id+) IgM and subsequently challenged with BCL1 tumor cells develop a state of tumor dormancy. The vast majority of dormant lymphoma cells are in cell cycle arrest, but there are also residual replicating cells. In the present studies, we attempted to define features of both the dormant lymphoma cells and the host that lead to escape from dormancy. Escape from dormancy occurs at a steady rate over a 2-year period, suggesting that it is a stochastic process. We found that, in the majority of mice, escape was due to the emergence of genetic variants that were no longer susceptible to the anti-Id-mediated induction of dormancy. Ten percent of these variants were Id-; the remainder were Id+ but could grow in the presence of anti-Id antibodies, suggesting that there were mutations in molecules involved in one or more mIg-mediated negative-signaling pathways. In two of five such escapees, alterations in either Syk, HS1, and/or Lyn were observed. In a small percentage of mice, a low titer of circulating anti-Id antibody before tumor challenge correlated with a subsequent, more rapid loss of dormancy.
Vitetta
E S
ES
Cancer Immunobiology Center and Department of Microbiology, University of Texas Southwestern Medical Center at Dallas, 75235, USA.
Tucker
T F
TF
Racila
E
E
Huang
Y W
YW
Marches
R
R
Lane
N
N
Scheuermann
R H
RH
Street
N E
NE
Watanabe
T
T
Uhr
J W
JW
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001798:Blood Proteins / Q000235:genetics / Q000502:physiology; D002453:Cell Cycle; D002455:Cell Division; D018450:Disease Progression; D004792:Enzyme Precursors / Q000235:genetics / Q000502:physiology; D007114:Immunization; D007130:Immunoglobulin Idiotypes / Q000276:immunology*; D007075:Immunoglobulin M / Q000276:immunology*; D007167:Immunotherapy; D047908:Intracellular Signaling Peptides and Proteins; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000276:immunology / Q000473:pathology* / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology; D009368:Neoplasm Transplantation; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics; D013163:Splenomegaly / Q000473:pathology; D013269:Stochastic Processes; D000072377:Syk Kinase; D013997:Time Factors; D019061:src-Family Kinases / Q000235:genetics / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; D001798:Blood Proteins; D004792:Enzyme Precursors; C061909:HCLS1 protein, human; D007130:Immunoglobulin Idiotypes; D007075:Immunoglobulin M; D047908:Intracellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases