Abstract
Syndecan-1 (CD138) is a heparan-sulfate proteoglycan (HSPG) known to be involved in cytokine signaling and cellular migration in the extracellular matrix. Knockout mice lacking CD138 expression exhibit a profound resistance to Wnt-1 induced mammary carcinoma that may be secondary to changes in mammary progenitor cell number or function. To determine whether this represented a more global phenomenon, we assessed the effects of CD138 expression on tumorigenesis induced by IP administration of the chemical carcinogen, DMBA, to post-natal mice. CD138−/− mice were highly resistant to DMBA-induced lung, liver, and ovarian carcinomas with an 80% reduction in tumor incidence compared to CD138+/+ mice. Absence of CD138 also protected from DMBA-induced hematopoietic tumors, with 4/58 (6.9%) KO versus 11/56 (19.6%) WT animals developing hematopoietic proliferations. Moreover, upon histologic and phenotypic analysis, the tumors arising in WT animals all proved to be CD4+CD8+ T-lymphoblastic lymphomas, which was seen in only a single KO animal. The other CD138−/− mice instead developed a myeloproliferative disorder with extensive splenic extramedullary hematopoiesis. We hypothesized that differences in tumor susceptibility between WT and KO mice may be secondary to abnormalities in tissue specific stem cell numbers and/or function. Therefore, we examined the expression and function of CD138 on mouse hematopoietic stem cells (HSC) and found that CD138 is expressed on approximately one third of mouse long-term HSC (LT-HSC), as defined by the Kit+Thy1.1loLin−Sca+ (KTLS) phenotype. Knockout mice lacking CD138 expression have mildly reduced numbers of HSC in the bone marrow with Lin−Sca+Kit+ cells making up 0.073±0.017% of marrow cells in CD138−/− mice versus 0.098±0.019% in WT mice (p = 0.038, n=6). While apparently adequate for hematopoiesis throughout the first 18 months of life, these HSC are functionally defective in competitive reconstitution assays in wild-type recipients compared to syngeneic, CD138+/+ LT-HSC. CD45.2+Kit+Flk2-Lin−Sca+ LT-HSC from CD138−/− or control CD138+/+ C57/Bl6 mice were flow sorted and 200 purified LT-HSC were injected into lethally irradiated CD45 congenic recipients along with 3 x 105 syngeneic whole bone marrow cells. Peripheral blood was monitored for reconstitution of T, B, and myeloid cells by analysis of CD45 allele expression; and as shown in the figure, LT-HSC from CD138−/− (KO) donor mice gave significantly less total leukocyte (p = 0.03 at 12 wks.) and myeloid (CD11b+ cells) reconstitution versus WT donor LT-HSC. These data suggest that CD138 plays a critical role in HSC function and provide a potential mechanism for the tumor resistant phenotype of CD138−/− mice. We are currently assessing function (in vivo and in vitro) of CD138 positive and negative WT KTLS-defined LT-HSC to determine whether CD138 may further subdivide this heterogeneous population.
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