Comparative analysis and anatomic distribution of ras p21, IL-2R, and MEL-14 in malignant and hyperplastic murine thymus.
The distribution and localization of thymocytes positive for p21 ras, the lymphocyte homing receptor antigen MEL-14, and IL-2 receptors were studied by immunohistology and flow cytometry. Comparisons were made between age-matched normal mice, carcinogen-treated mice at early (stage II) and late (stage III) stages of disease, and cortisone-treated mice. In normal thymus, the majority of cortical and medullary thymocytes are p21 ras positive. MEL-14hi- and IL-2R-positive cells are located in the cortex and comprise less than 5% of the thymus population. Stage II carcinogen-treated animals consistently show increased numbers of MEL-14hi cells in the thymus, with fewer animals having increased numbers of IL-2R positive cells. These populations appear to be different from one another. All stage III animals have MEL-14hi-positive tumor cells, which in 70% of the cases also express IL-2R. Cortisone treatment was used to study non-malignant proliferation. After cortisone treatment there is a marked increase of p21 ras staining in both the cortex and medulla during the first 72-hour interval. Within 24 hours, 50% of the thymocytes are IL-2R positive, but MEL-14hi cells are not detected. By 48 hours, 90% of the thymus population expresses IL-2R and 50% of the cells are MEL-14hi positive, and this results in a substantial population of cells positive for both IL-2R positive:MEL-14hi markers. This population rapidly disappears by 72 hours, leaving 90% of the cells MEL-14hi positive and less than 10% IL-2R positive. The staining of p21 ras at 72 hours is unusual, showing a speckled, cytoplasmic pattern. In light of our findings, we propose that the first step in thymic lymphomagenesis in carcinogen-treated C57BL/6 mice involves the rare cortical MEL-14hi subpopulation and is thymic dependent. A late stage involves expression of IL-2 receptors by a subset of MEL-14hi cells, thus conferring the potential for autonomous growth and malignancy.
Department of Pathology, New York University, New York 10016.
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Newcomb
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Pellicer
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Cordon
D000818:Animals; D003348:Cortisone / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D006965:Hyperplasia / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D008223:Lymphoma / Q000139:chemically induced / Q000378:metabolism; D008770:Methylnitrosourea / Q000494:pharmacology; D051379:Mice; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras); D011971:Receptors, Immunologic / Q000378:metabolism*; D015375:Receptors, Interleukin-2 / Q000378:metabolism*; D016201:Receptors, Lymphocyte Homing; D013950:Thymus Gland / Q000378:metabolism* / Q000528:radiation effects / Q000648:ultrastructure; D013953:Thymus Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure
D011518:Proto-Oncogene Proteins; D011971:Receptors, Immunologic; D015375:Receptors, Interleukin-2; D016201:Receptors, Lymphocyte Homing; D008770:Methylnitrosourea; D016283:Proto-Oncogene Proteins p21(ras); D003348:Cortisone