Juvenile syndecan-1 null mice are protected from carcinogen-induced tumor development

Abstract

We previously showed that mice with a null mutation in syndecan-1 (Sdc1; CD138) were resistant to Wnt1-induced mammary tumor initiation. The absence of Sdc1 inhibited the increase in the mammary stem cell fraction that is characteristic of preneoplasia in this model. As the tumor precursor cells are recruited from the stem/ progenitor cell compartment, tumor development was also inhibited (Liu et al., 2004; PNAS 101, 4158). Although Sdc1À/À mice are grossly normal, they are systemically smaller, suggesting that developmental abnormalities may extend further than their mammary glands. We have therefore evaluated the multi-organ response of Sdc1À/À mice to carcinogen-induced tumor development (7,12-dimethylbenz[a]anthracene, DMBA), and find these mice to be resistant to tumorigenesis in all the predominant carcinogen-susceptible lineages. Thus, Sdc1À/À mice administered DMBA during juvenile development are resistant not only to epithelial tumors, including liver (60-80%) and lung tumors (C57BL6 mice, 60-80%), but also to lymphoma (over 70%, depending upon strain and carcinogen dose). We demonstrate that CD138 is expressed (heterogeneously) in the hematopoietic stem cell fraction (and not only in pre-B and plasma cells), and that tumors arise in both myeloid and lymphoid lineages. Furthermore, carcinogen-induced mammary tumors are bilineal, implying a bipotent precursor cell. Both observations imply that the DMBA-induced tumor precursor cells are drawn from the stem/progenitor fraction, and we suggest that pathogenic activation of these cells could be abnormal in Sdc1À/À mice.

Syndecan-1, a Cell Surface Proteoglycan, Negatively Regulates Initial Leukocyte Recruitment to the Brain across the Choroid Plexus in Murine Experimental Autoimmune Encephalomyelitis

“…Most studies report enhanced immune cell infiltration in Sdc-1 2/2 mice, which has been correlated with enhanced extravasation from postcapillary venules because of effects ranging from modulation of integrin activity and interaction with cell adhesion molecules (14,15) to modulation of cytokine and chemokine gradients (16). Yet, the expression of syndecan-1 on endothelium and immune cells in vivo is difficult to detect, with the notable exception of B lymphocytes, which may be partially because of its dynamic regulation (9,(17)(18)(19).…”

Role of the Heparan Sulfate Proteoglycan Syndecan-1 (CD138) in Delayed-Type Hypersensitivity

“…Highly conserved cytoplasmic phosphorylation sites participate in signaling events modulating cell adhesion and migration (11,12). The major functional domain of the Sdc ectodomains are their heparan sulfate chains, which specifically bind to a large number of extracellular ligands active in morphogenesis, tissue repair, host defense, tumor development, and inflammation (10,(13)(14)(15)(16)(17). Sdcs play a major role as matrix and cell surface receptors, coreceptors for growth factor and chemokine signaling, internalization receptors, and as soluble paracrine effectors upon cleavage of their extracellular domain by matrix metalloproteinases (10,18).…”

“…In the adult, Sdc-1 is expressed in epithelia, endothelia, and several leukocyte subgroups including pre-B cells and plasma cells, macrophages, and hematopoietic stem cells (7,17,19). Using KO and transgenic mouse models, we and others could recently demonstrate a role for Sdc-1 in regulating inflammation in a variety of disease models: Sdc-1 KO mice show increased adhesion of leukocytes to retinal blood vessels under unstimulated conditions and massively increased leukocyte adhesion and transendothelial diapedesis following TNF-␣ stimulation of mesenteric blood vessels (20).…”

Endometrial Cells Get Side-Tracked

“…11 For example, mice deficient in the cell surface proteoglycan syndecan-1 (CD138), a molecular marker associated with epithelial-mesenchymal transition during development and carcinogenesis, 12 were shown to be resistant to a variety of experimentally induced cancers due to a reduction in a wnt-responsive progenitor cell population. 11,13 In human endometrial carcinoma, low epithelial CD138 expression is correlated with negative prognostic factors and disease stage, whereas stromal CD138 expression was shown to be significantly higher in high-grade tumors and to be an independent prognostic factor for both disease-free and overall survival.…”