Downregulation of interleukin-7 and hepatocyte growth factor in the thymic microenvironment is associated with thymus involution in tumor-bearing mice

Roberto Carrio, Norman H. Altman, Diana M Lopez

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

During mammary tumorigenesis, there is a profound thymic involution associated with severe depletion of the most abundant subset of thymocytes, CD4 +CD8 +immature cells, and an early arrest in at least two steps of T cell differentiation. Thymic atrophy that is normally related with aging has been observed in other model systems, including graft-vs-host disease (GVHD) and tumor development. However, the mechanisms involved in this phenomenon remain to be elucidated. Vascular endothelial growth factor (VEGF) has been associated with thymic involution, when expressed at high levels systemically. In thymuses of D1-DMBA-3 tumor-bearing mice, this growth factor is diminished relative to the level of normal thymuses. Interestingly, the expression of hepatocyte growth factor (HGF), which has been associated with proliferation, cell survival, angiogenesis and B-cell differentiation, is profoundly down-regulated in thymuses of tumor bearers. In parallel, IL-7 and IL-15 mRNA, crucial cytokines involved in thymocytes development and cellular homeostasis, respectively, are also down-regulated in the thymuses of tumor hosts as compared to those of normal mice. Injection of HGF into mice implanted with mammary tumors resulted in normalization of thymic volume and levels of VEGF, IL-7 and IL-15. While, injections of IL-7 partially restored the thymic involution observed in the thymuses of tumor-bearing mice, injection of IL-15 did not have any significant effects. Our data suggest that the downregulation of HGF and IL-7 may play an important role in the thymic involution observed in tumor-bearing hosts.

Original languageEnglish
Pages (from-to)2059-2072
Number of pages14
JournalCancer Immunology, Immunotherapy
Volume58
Issue number12
DOIs
StatePublished - Dec 1 2009

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Interleukin-7
Hepatocyte Growth Factor
Thymus Neoplasms
Interleukin-15
Thymus Gland
Down-Regulation
Thymocytes
Vascular Endothelial Growth Factor A
Injections
Cell Differentiation
Neoplasms
9,10-Dimethyl-1,2-benzanthracene
Graft vs Host Disease
Atrophy
Cell Survival
Intercellular Signaling Peptides and Proteins
Carcinogenesis
Breast
Homeostasis
B-Lymphocytes

Keywords

  • Hepatocyte growth factor
  • IL-7
  • Thymus
  • Tumor-bearing mice
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Immunology
  • Immunology and Allergy
  • Medicine(all)

Cite this

Downregulation of interleukin-7 and hepatocyte growth factor in the thymic microenvironment is associated with thymus involution in tumor-bearing mice. / Carrio, Roberto; Altman, Norman H.; Lopez, Diana M.

In: Cancer Immunology, Immunotherapy, Vol. 58, No. 12, 01.12.2009, p. 2059-2072.

Research output: Contribution to journalArticle

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AB - During mammary tumorigenesis, there is a profound thymic involution associated with severe depletion of the most abundant subset of thymocytes, CD4 +CD8 +immature cells, and an early arrest in at least two steps of T cell differentiation. Thymic atrophy that is normally related with aging has been observed in other model systems, including graft-vs-host disease (GVHD) and tumor development. However, the mechanisms involved in this phenomenon remain to be elucidated. Vascular endothelial growth factor (VEGF) has been associated with thymic involution, when expressed at high levels systemically. In thymuses of D1-DMBA-3 tumor-bearing mice, this growth factor is diminished relative to the level of normal thymuses. Interestingly, the expression of hepatocyte growth factor (HGF), which has been associated with proliferation, cell survival, angiogenesis and B-cell differentiation, is profoundly down-regulated in thymuses of tumor bearers. In parallel, IL-7 and IL-15 mRNA, crucial cytokines involved in thymocytes development and cellular homeostasis, respectively, are also down-regulated in the thymuses of tumor hosts as compared to those of normal mice. Injection of HGF into mice implanted with mammary tumors resulted in normalization of thymic volume and levels of VEGF, IL-7 and IL-15. While, injections of IL-7 partially restored the thymic involution observed in the thymuses of tumor-bearing mice, injection of IL-15 did not have any significant effects. Our data suggest that the downregulation of HGF and IL-7 may play an important role in the thymic involution observed in tumor-bearing hosts.

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