Decorin is not only a regulator of matrix assembly but also a key signaling molecule that modulates the activity of tyrosine kinase receptors such as the epidermal growth factor receptor (EGFR). Decorin evokes protracted internalization of the EGFR via a caveolar-mediated endocytosis, which leads to EGFR degradation and attenuation of its signaling pathway. In this study, we tested if systemic delivery of decorin protein core would affect the biology of an orthotopic squamous carcinoma xenograft. After tumor engraftment, the animals were given intraperitoneal injections of either vehicle or decorin protein core (2.5-10 mg kg ؊1 ) every 2 days for 18 -38 days. This regimen caused a significant and dose-dependent inhibition of the tumor xenograft growth, with a concurrent decrease in mitotic index and a significant increase in apoptosis. Positron emission tomography showed that the metabolic activity of the tumor xenografts was significantly reduced by decorin treatment. Decorin protein core specifically targeted the tumor cells enriched in EGFR and caused a significant downregulation of EGFR and attenuation of its activity. In vitro studies showed that the uptake of decorin by the A431 cells was rapid and caused a protracted down-regulation of the EGFR to levels similar to those observed in the tumor xenografts. Furthermore, decorin induced apoptosis via activation of caspase-3. This could represent an additional mechanism whereby decorin might influence cell growth and survival.The growth of human cancer cells is often dependent or facilitated by the overexpression of receptor tyrosine kinase, such as the EGFR, 2 that provide a growth advantage to the growing and infiltrating neoplasms (1). To prevent the dire consequences of uncontrolled activation of EGFR, a number of negative feedback mechanisms, both extracellular and intracellular, have evolved (2, 3). The prominent role of the EGFR as a crucial relay station among various inputs from the environment and cellular responses has raised the significance of this signaling-transducing receptor to a new level and offers new possibilities for therapeutic intervention (4). We have previously shown that decorin, a secreted small leucine-rich proteoglycan (5, 6), is capable of suppressing the growth of tumor cells with various histogenetic backgrounds (7, 8) by directly interacting with the EGFR (9 -11). Decorin evokes a protracted down-regulation of EGFR tyrosine kinase (12) and other members of the ErbB family of receptor tyrosine kinase (13) and causes an attenuation of the EGFR-mediated mobilization of intracellular calcium (12). Decorin induces expression of the endogenous cyclin-dependent kinase inhibitor p21 WAF1 (14, 15) and a subsequent arrest of the cells in the G 1 phase of the cell cycle (7). These growthsuppressive properties of the soluble decorin and its protein core can also affect murine tumor cells (8) and normal human cells, such as endothelial cells (16) and macrophages (17). A number of observations point toward a key role for decorin in the cont...

Background One of the greatest impediments to cancer immunotherapy is the paucity of antigens that are tumor-specific, sufficiently immunogenic, and shared among patients. Mucosa-restricted antigens that are expressed by tumor cells represent a novel class of vaccine targets exploiting immunologic privilege, which limits systemic tolerance to those antigens, and immunologic partitioning, which shields mucosae from systemic autoimmune responses. Here we defined the immunogenicity and antitumor efficacy of guanylyl cyclase C (GCC), a protein that is normally restricted to intestinal mucosa and universally expressed by metastatic colorectal cancer. Methods BALB/c mice (n=197) were immunized with recombinant viral vectors before (prophylactic) or after (therapeutic) a lethal challenge of GCC-expressing mouse colon cancer cells, and antitumor efficacy was monitored by quantifying metastasis and survival. Induction of autoimmunity was monitored by histopathology. Induction of GCC-specific B cell and CD4+ and CD8+ T cell responses were determined by enzyme-linked immunosorbent assay (ELISA) and ELISpot, respectively. Tolerance to GCC was quantified by comparing responses in GCC-deficient (n=45) and wild-type (n=69) C57BL/6 mice. Statistical tests were two-sided. Results Immunization with GCC-expressing viral vectors reduced the formation of metastases to liver (control vs GCC: mean = 30.4 vs 3.55 nodules, difference = 26.9 nodules, 95% confidence interval [CI] = 8.47 to 45.3 nodules; P = .008) and lung (control vs GCC: mean =263 vs 55.7 nodules, difference = 207, 95% CI = 163 to 251; P < .001) and extended the median survival of mice with established lung metastases following therapeutic immunization (control vs GCC: 29 vs 38 days, P = .024), without autoimmunity. Antitumor efficacy reflected asymmetric tolerance that was characterized by CD8+ T cell, but not CD4+ T cell or antibody, responses. Conclusions Immunologic partitioning together with immunologic privilege highlight the potential of mucosa-restricted antigens, particularly GCC, as therapeutic targets for metastatic cancer.

Detection of SLNs with lymphatic US compared favorably with that at lymphoscintigraphy. Lymphatic US can depict metastases within the SLN, which was not possible with lymphoscintigraphy.

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Decorin, a member of the small leucine-rich proteoglycan gene family, down-regulates members of the ErbB receptor tyrosine kinase family and attenuates their signaling, leading to growth inhibition. We investigated the effects of decorin on the growth of ErbB2-overexpressing mammary carcinoma cells in comparison with AG879, an established ErbB2 kinase inhibitor. Cell proliferation and anchorage-independent growth assays showed that decorin was a potent inhibitor of breast cancer cell growth and a pro-apoptotic agent. When decorin and AG879 were used in combination, the inhibitory effect was synergistic in proliferation assays but only additive in both colony formation and apoptosis assays. Active recombinant human decorin protein core, AG879, or a combination of both was administered systemically to mice bearing orthotopic mammary carcinoma xenografts. Primary tumor growth and metabolism were reduced by approximately 50% by both decorin and AG879. However, no synergism was observed in vivo. Decorin specifically targeted the tumor cells and caused a significant reduction of ErbB2 levels in the tumor xenografts. Most importantly , systemic delivery of decorin prevented metastatic spreading to the lungs , as detected by novel species-specific DNA detection and quantitative assays. In contrast , AG879 failed to have any effect. Our data support a role for decorin as a powerful and effective therapeutic agent against breast cancer due to its inhibition of both primary tumor growth and metastatic spreading.