Mice with a null mutation in the cell surface heparan sulfate (HS) proteoglycan, syndecan-1 (Sdc1), develop almost normally, but resist mammary tumor development in response to Wnt-1. Here, we test the hypothesis that Sdc1 promotes Wnt-1-induced tumor development by interacting with the Wnt cell surface signaling complex. Thus, the response of Sdc1À/À mammary epithelial cells (mecs) to the intracellular, activated Wnt signal transducer, DNb-catenin, was assayed both in vitro and in vivo, to test whether b-catenin/TCF transactivation was Sdc1-independent. Surprisingly, we found that the expression of a canonical Wnt pathway reporter, TOP-FLASH, was reduced by 50% in both unstimulated Sdc1À/À mecs and in stimulated cells responding to Wnt1 or DNb-catenin. Tumor development in response to DNb-catenin was also significantly delayed on a Sdc1À/À background. Furthermore, the average b-catenin/TCF transactivation per cell was normal in Sdc1À/À mec cultures, but the number of responsive cells was reduced by 50%. Sdc1À/À mecs show compensatory changes that maintain the number of HS chains, hence these experiments cannot test the coreceptor activity of HS for Wnt signaling. We propose that TCF-dependent transactivational activity is suppressed in 50% of cells in Sdc1À/À glands, and conclude that the major effect of Sdc1 does not map to the activity of the Wnt signaling complex, but to another pathway to create or stabilize the b-catenin/TCF-responsive tumor precursor cells in mouse mammary gland.
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.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.