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

Oncogene volume 26, pages 1407–1416 (2007)Cite this article

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 Sdc1−/− 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 Sdc1−/− 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, Sdc1−/− 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 Sdc1−/− mice.

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Abbreviations

Sdc1(CD138):

syndecan-1

DMBA:

7,12-dimethylbenz[a]anthracene

Ahr:

aryl hydrocarbon receptor

MMTV:

mouse mammary tumor virus

EROD:

ethoxyresorufin O-deethylase

HSCs:

hematopoietic stem cells

ENU:

N-ethyl-N-nitrosurea

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Acknowledgements

We thank Dr Henry Pitot (McArdle Laboratory, UW-Madison) for histological analysis of liver tumors; Dr Norman Drinkwater (McArdle Laboratory) for help with statistical analyses; Jane Weeks and Harlene Edwards at the McArdle Histology core; Joel Puchalski and Kathy Schell at the UW Flow Facility for their expertise; members of Dr Chris Bradfield's lab (McArdle Laboratory) for help with the EROD assay; Kelly Moore and Melissa Mastroianni for assistance with genotyping and immunohistochemical staining; Tianxing Liu for maintenance of our mouse colonies; and members of the Alexander lab for helpful discussions. This study was supported by the National Institutes of Health (CA 90877), the Susan Komen Foundation (BCTR 0202106) and the UW Cancer Center and the Cancer Biology Training Program (SPM; T32 CA09135).

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Author notes

  1. S P McDermott and E A Ranheim: These two authors contributed equally to this work.

Authors and Affiliations

  1. McArdle Laboratory for Cancer Research, University of Wisconsin-Madison Medical School, Madison, WI, USA

    S P McDermott, V S Leatherberry, S S Khwaja, K S Klos & C M Alexander

  2. Department of Pathology, University of Wisconsin-Madison Medical School, Madison, WI, USA

    E A Ranheim

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  1. S P McDermott
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Correspondence to C M Alexander.

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Supplementary Information accompanies the paper on oncogene website (http://www.nature.com/onc).

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McDermott, S., Ranheim, E., Leatherberry, V. et al. Juvenile syndecan-1 null mice are protected from carcinogen-induced tumor development. Oncogene 26, 1407–1416 (2007). https://doi.org/10.1038/sj.onc.1209930

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