Juvenile syndecan-1 null mice are protected from carcinogen-induced tumor development.
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.
McDermott
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McArdle Laboratory for Cancer Research, University of Wisconsin-Madison Medical School, Madison, WI 53706, USA.
Ranheim
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Leatherberry
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Khwaja
S S
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Klos
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Alexander
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D015127:9,10-Dimethyl-1,2-benzanthracene; D000367:Age Factors; D000818:Animals; D049628:Body Size; D002273:Carcinogens; D005260:Female; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000139:chemically induced / Q000517:prevention & control*; D053668:Syndecan-1 / Q000502:physiology*
D002273:Carcinogens; C508242:Sdc1 protein, mouse; D053668:Syndecan-1; D015127:9,10-Dimethyl-1,2-benzanthracene