Supplementary Table S1 from Identification of SFRP1 as a Candidate Mediator of Stromal-to-Epithelial Signaling in Prostate Cancer

Supplementary Tables 1-3, Figure 1 from Targeting the Lymphotoxin-β Receptor with Agonist Antibodies as a Potential Cancer Therapy

Supplementary Table S2 from Identification of <i>SFRP1</i> as a Candidate Mediator of Stromal-to-Epithelial Signaling in Prostate Cancer

Knowledge of resource-use and movement patterns is a missing component in the development of horseshoe crab (Limulus polyphemus) management strategies. Available evidence indicates the potential for a variety of possible migratory behaviors, but the lack of high-resolution, spatial-temporal data has hindered development of a year-round profile of ranging behavior. This need was addressed in the present study by using acoustic telemetry to track the movements of adult horseshoe crabs in two subembayments (Egypt and Hog Bays) of the Taunton Bay Estuary, Maine, from June 2003 to June 2005. Estimated mean total home range sizes were 64.1 and 61.4 ha for breeding crabs tagged in Egypt and Hog Bays, respectively. We observed no horseshoe crab dispersal to areas outside of the subembayments where they were tagged, so no mixing was observed between Egypt and Hog Bay individuals despite a < 4-km separation. Observed shifts in movement patterns, resource use (subtidal versus intertidal), and vagility facilitated a profile of seasonally partitioned horseshoe crab activity, which included late April to early May post-wintering, June–July breeding, August–September pre-wintering, and October–April wintering, where space usage represented about 10% of the mean total home range size. The apparent isolation of these resident populations implies a heightened vulnerability to overexploitation and large-scale habitat alteration that might be more easily sustained by larger, more vagile populations. This work underscores the need to apply horseshoe crab conservation, research, and management efforts at scales that are appropriate to the ranging patterns of crabs, which first requires application of high-resolution methods to identify those patterns.

Abstract The lymphotoxin-β receptor (LTβR) is a tumor necrosis factor receptor family member critical for the development and maintenance of various lymphoid microenvironments. Herein, we show that agonistic anti-LTβR monoclonal antibody (mAb) CBE11 inhibited tumor growth in xenograft models and potentiated tumor responses to chemotherapeutic agents. In a syngeneic colon carcinoma tumor model, treatment of the tumor-bearing mice with an agonistic antibody against murine LTβR caused increased lymphocyte infiltration and necrosis of the tumor. A pattern of differential gene expression predictive of cellular and xenograft response to LTβR activation was identified in a panel of colon carcinoma cell lines and when applied to a panel of clinical colorectal tumor samples indicated 35% likelihood a tumor response to CBE11. Consistent with this estimate, CBE11 decreased tumor size and/or improved long-term animal survival with two of six independent orthotopic xenografts prepared from surgical colorectal carcinoma samples. Targeting of LTβR with agonistic mAbs offers a novel approach to the treatment of colorectal and potentially other types of cancers. (Cancer Res 2006; 66(19): 9617-24)

Abstract Genetic changes in epithelial cells initiate the development of prostatic adenocarcinomas. As nascent tumors grow and undergo progression, epithelial tumor cells are intimately associated with stromal cells. Stromal cells within the tumor microenvironment acquire new properties, including the capacity to promote phenotypic and genetic progression in adjacent epithelial cells. Affymetrix microarrays were used to identify 119 genes differentially expressed between normal-derived and carcinoma-derived prostatic stromal cells. These included 31 genes encoding extracellular proteins that may act as stromal-to-epithelial paracrine signals. Further investigation of one of these genes, secreted frizzled related protein 1 (SFRP1), revealed that its expression parallels prostatic growth with high expression during prostatic development, low expression in the adult prostate, and elevated expression in prostatic tumor stroma. In addition, as prostatic epithelial cells progressed to a tumorigenic state under the influence of tumor stroma, SFRP1 became overexpressed in the progressed epithelial cells. To further understand the roles of SFRP1 in the prostate, we tested the affects of increased SFRP1 levels on prostatic tissues and cells. Treatment of developing prostates with SFRP1 in culture led to increased organ growth. Treatment of a human prostatic epithelial cell line with SFRP1 led to increased proliferation, decreased apoptosis, and decreased signaling through the Wnt/β-catenin pathway in vitro and increased proliferation in vivo. These data suggest that overexpression of SFRP1 by prostatic tumor stroma may account for the previously reported capacity of prostatic tumor stroma to provide a pro-proliferative paracrine signal to adjacent epithelial cells.

Axon regeneration in the adult CNS is prevented by inhibitors in myelin. These inhibitors seem to modulate RhoA activity by binding to a receptor complex comprising a ligand-binding subunit (the Nogo-66 receptor NgR1) and a signal transducing subunit (the neurotrophin receptor p75). However, in reconstituted non-neuronal systems, NgR1 and p75 together are unable to activate RhoA, suggesting that additional components of the receptor may exist. Here we describe LINGO-1, a nervous system-specific transmembrane protein that binds NgR1 and p75 and that is an additional functional component of the NgR1/p75 signaling complex. In non-neuronal cells, coexpression of human NgR1, p75 and LINGO-1 conferred responsiveness to oligodendrocyte myelin glycoprotein, as measured by RhoA activation. A dominant-negative human LINGO-1 construct attenuated myelin inhibition in transfected primary neuronal cultures. This effect on neurons was mimicked using an exogenously added human LINGO-1-Fc fusion protein. Together these observations suggest that LINGO-1 has an important role in CNS biology.