Homing and mobilization of hematopoietic stem cells and hematopoietic cancer cells are mirror image processes, utilizing similar signaling pathways and occurring concurrently: circulating cancer cells constitute an ideal target for concurrent treatment with chemotherapy and antilineage-specific antibodies.
Adhesion molecules and stromal cell-derived factor-1 (SDF-1)/CXCR4 signaling play key role in homing and mobilization of hematopoietic progenitor (HPC) and hematopoietic cancer clonogenic cells (HCC). High expression of VLA-4 is required for homing of HPC and HCC, whereas downregulation of these molecules is required for successful mobilization of HPC and HCC. Upregulation and activation of the SDF-1/CXCR4 signaling is required for homing of HPC and HCC, whereas disruption of the SDF-1 signaling is required for mobilization of HPC and HCC. Hence, mobilizations of HPC and HCC occur concurrently. It is proposed that drug resistance evolves as a result of repeated cycles of chemotherapy. Following each cycle of chemotherapy, HCC lose adhesion molecules and SDF-1 signaling. Surviving cells, released from tumor sites, circulate until re-expression of adhesion molecules and CXCR4 occurs, then homing to stroma of distal tissues occurs. Cytokines secreted by cells in the new microenvironment induce proliferation and drug resistance of HCC. This process is amplified in each cycle of chemotherapy resulting in disease progression. A novel model for treatment is proposed in which circulating HCC are the target for clinical intervention, and concurrent treatment with chemotherapy and antilineage-specific antibodies will result in abrogation of the 'vicious cycle' of conventional anticancer therapy.
Gazitt
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Y
University of Texas Health Science Center, San Antonio, TX 78284, USA.
D000970:Antineoplastic Agents / Q000627:therapeutic use; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000502:physiology; D002465:Cell Movement / Q000502:physiology*; D018925:Chemokines / Q000502:physiology; D019337:Hematologic Neoplasms / Q000378:metabolism / Q000628:therapy*; D019650:Hematopoietic Stem Cell Mobilization; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects; D006801:Humans; D009360:Neoplastic Cells, Circulating; D019718:Receptors, CXCR4 / Q000502:physiology; D015398:Signal Transduction
D000970:Antineoplastic Agents; D015815:Cell Adhesion Molecules; D018925:Chemokines; D019718:Receptors, CXCR4