Interleukin 1, an immune response-generated cytokine that stimulates astrocyte proliferation and reactivity (astrogliosis), was present in up to 30 times as many glial cells in tissue sections of brain from patients with Down syndrome and Alzheimer disease compared with age-matched control subjects. Most interleukin 1-immunoreactive glia in Down syndrome and Alzheimer disease were classified as microglia. The number of interleukin 1 immunoreactive neurons did not appear to differ in Down syndrome and Alzheimer disease compared with control brain. Numerous temporal lobe astrocytes in Alzheimer disease and postnatal Down syndrome were intensely interleukin 1-, S-100-, and glial fibrillary acidic protein-immunoreactive and had reactive structure. Interleukin 1 levels in Alzheimer disease temporal lobe homogenates were elevated, as were the levels of S-100 and glial fibrillary acidic protein, two proteins reportedly elevated in reactive astrocytes. These data suggest that increased expression of S-100 in Down syndrome, resulting from duplication of the gene on chromosome 21 that encodes the I6 subunit of S-100, may be augmented by elevation of interleukin 1. As a corollary, the astrogliosis in Alzheimer disease may be promoted by elevation of interleukin 1.

When shed from the cell surface, the heparan sulfate proteoglycan syndecan-1 can facilitate the growth, angiogenesis, and metastasis of tumors. Here we report that tumor cell expression of heparanase, an enzyme known to be a potent promoter of tumor progression and metastasis, regulates both the level and location of syndecan-1 within the tumor microenvironment by enhancing its synthesis and subsequent shedding from the tumor cell surface. Heparanase regulation of syndecan-1 is detected in both human myeloma and breast cancer cell lines. This regulation requires the presence of active enzyme, because mutated forms of heparanase lacking heparan sulfate-degrading activity failed to influence syndecan-1 expression or shedding. Removal of heparan sulfate from the cell surface using bacterial heparitinase dramatically accelerated syndecan-1 shedding, suggesting that the effects of heparanase on syndecan-1 expression by tumor cells may be due, at least in part, to enzymatic removal or reduction in the size of heparan sulfate chains. Animals bearing tumors formed from cells expressing high levels of heparanase or animals transgenic for heparanase expression exhibited elevated levels of serum syndecan-1 as compared with controls, indicating that heparanase regulation of syndecan-1 expression and shedding can occur in vivo and impact cancer progression and perhaps other pathological states. These results reveal a new mechanism by which heparanase promotes an aggressive tumor phenotype and suggests that heparanase and syndecan-1 act synergistically to fine tune the tumor microenvironment and ensure robust tumor growth.

To participate as co-receptor in growth factor signaling, heparan sulfate must have specific structural features. Recent studies show that when the levels of 6-O-sulfation of heparan sulfate are diminished by the activity of extracellular heparan sulfate 6-O-endosulfatases (Sulfs), fibroblast growth factor 2-, heparin binding epidermal growth factor-, and hepatocyte growth factor-mediated signaling are attenuated. This represents a novel mechanism for regulating cell growth, particularly within the tumor microenvironment where the Sulfs are known to be misregulated. To directly test the role of Sulfs in tumor growth control in vivo, a human myeloma cell line was transfected with cDNAs encoding either of the two known human endosulfatases, HSulf-1 or HSulf-2. When implanted into severe combined immunodeficient (SCID) mice, the growth of these tumors was dramatically reduced on the order of 5-to 10-fold as compared with controls. In addition to an inhibition of tumor growth, these studies revealed the following. Heparan sulfate proteoglycans act as co-receptors for numerous heparin-binding growth factors and cytokines and are thus key regulators of cell signaling (1). Previous studies have demonstrated that growth factor binding to heparan sulfate and the resulting mitogenic activity occur only when specific structural features are present within the heparan sulfate chains. These features include sulfation at specific positions within a disaccharide (N, 2-O, 3-O, 6-O) by the enzymes that orchestrate heparan sulfate synthesis within the Golgi (2). However, recent studies show that following its synthesis and expression, heparan sulfate can also be structurally and functionally modified within the extracellular compartment. The two enzymes presently known to have these effects are heparanase, which cleaves heparan sulfate chains into small, biologically active fragments, and the heparan sulfate 6-O-endosulfatases (Sulfs).2 Sulfs represent a newly discovered family of enzymes that are secreted via the Golgi and become localized to the cell surface or are released into the extracellular matrix. These enzymes selectively remove the 6-O-sulfate groups from heparan sulfate with preference for the 6-O-sulfates present on trisulfated disaccharides (3, 4).The first member of the endosulfatase family to be described was sulfatase-1 from quail (QSulf1), where the activity of this enzyme is required for Wnt-mediated signaling in developing muscle (5). In separate studies, Qsulf1 was shown to restore bone morphogenetic protein signaling in cells by releasing its functional inhibitor, Noggin, from cell surfaces (3). In contrast, QSulf1 can also inhibit growth factor signaling, as removal of the 6-O-sulfation required for the formation of the FGF⅐HS⅐FR1c ternary complex blocks FGF2 signaling (6). Thus, the Sulfs can have activities that promote or inhibit growth factor signaling depending on the specific factor involved.In addition to quail, the Sulf-1 enzyme has also been cloned from rat, mouse, and human, and a second family me...

The heparan sulfate proteoglycan syndecan-1 is expressed by myeloma cells and shed into the myeloma microenvironment. High levels of shed syndecan-1 in myeloma patient sera correlate with poor prognosis and studies in animal models indicate that shed syndecan-1 is a potent stimulator of myeloma tumor growth and metastasis. Overexpression of extracellular endosulfatases, enzymes which remove 6-O sulfate groups from heparan sulfate chains, diminishes myeloma tumor growth in vivo. Together, these findings identify syndecan-1 as a potential target for myeloma therapy. Here, 3 different strategies were tested in animal models of myeloma with the following results: (1) IntroductionSyndecan-1 (CD138) is a cell-surface heparan sulfate-bearing proteoglycan that was first detected by polymerase chain reaction (PCR) in mRNA from human patients with myeloma and later confirmed by monoclonal antibody staining to be present on all myeloma tumors. 1,2 Syndecan-1 is shed from the myeloma tumor cell surface and accumulates in the bone marrow and serum of patients. When present at high levels in the serum, syndecan-1 is an independent indicator of poor prognosis. [3][4][5] However, high-serum syndecan-1 is more than simply an indicator of poor prognosis. Studies in animal models have shown that high levels of soluble syndecan-1 enhance both the growth and metastasis of tumors. 6 Syndecan-1 exerts its growth-promoting effects by regulating the activity of many effector molecules important for myeloma growth and survival, including hepatocyte growth factor (HGF) and heparin-binding epidermal growth factor (HB-EGF) family members, among others. 7,8 The high levels of heparan sulfate in the tumor microenvironment resulting from syndecan-1 shedding also act as positive regulators that condition the microenvironment for robust tumor growth. For example, heparan sulfate binds to and promotes the activity of important angiogenic growth factors such as fibroblast growth factor-2 (FGF-2) and vascular endothelial growth factor (VEGF). This activity can occur in trans, indicating that shed syndecan-1 can contribute to the high level of angiogenesis seen in many patients with myeloma. 9,10 In addition, the syndecan-1 that becomes embedded within the myeloma tumor stroma can serve as reservoir for storage and concentration of heparan sulfate-binding growth factors that can later be mobilized by cleavage of the heparan sulfate by heparanase. 3,11 This mobilization of heparan sulfate-retained growth factors in the bone marrow likely contributes to the high rate of relapse among patients with myeloma.Because of its high level of expression on myeloma tumors, syndecan-1 has been explored as a candidate antigen for antibody targeting of toxins to the tumor cell surface. [12][13][14] In addition, antibodies to syndecan-1 show promise as facilitators of myeloma immunotherapeutic approaches. 15 However, specific strategies for disrupting the function of syndecan-1 or its heparan sulfate chains as a potential therapy for myeloma have not been reported...

Heparan sulfate proteoglycans (HSPGs), via their interactions with numerous effector molecules such as FGF-2, IL-8, and VEGF, regulate the biological activity of cells by acting as co-receptors that promote signaling. The extent and nature of their role as co-receptors is often misregulated in cancer as manifested by alterations in HSPG structure and expression level. This misregulation of HSPGs can aid in promoting the malignant phenotype. In addition to expressionrelated changes in HSPGs, recent discoveries indicate that HSPGs localized within the tumor microenvironment can be attacked by enzymes that alter proteoglycan structure resulting in dramatic effects on tumor growth and metastasis. This review focuses on remodeling of HSPGs by three distinct mechanisms that occur in vivo; (i) shedding of proteoglycan extracellular domains from cell surfaces, (ii) fragmentation of heparan sulfate chains by heparanase, and (iii)