Tumor-derived inducible heat-shock protein 70 (HSP70) is an essential component of anti-tumor immunity.

Abstract

The anti-apoptotic function and tumor-associated expression of heat-shock protein 70 (HSP70) is consistent with HSP70 functioning as a survival factor to promote tumorigenesis. However, its immunomodulatory activities to induce anti-tumor immunity predict the suppression of tumor growth. Using the Hsp70.1/3(-/-)(Hsp70(-/-)) mouse model, we observed that tumor-derived HSP70 was neither required for cellular transformation nor for in vivo tumor growth. Hsp70(-/-) murine embryonic fibroblasts (MEFs) were transformed by E1A/Ras and generated tumors in immunodeficient hosts as efficiently as wild-type (WT) transformants. Comparison of Bcr-Abl-mediated transformation of WT and Hsp70(-/-) bone marrow and progression of B-cell leukemogenesis in vivo revealed no differences in disease onset or survival rates, and Eμ-Myc-driven lymphoma in Hsp70(-/-) mice was phenotypically indistinguishable from that in WT Eμ-Myc mice. However, Hsp70(-/-) E1A/Ras MEFs generated significantly larger tumors than their WT counterparts in C57BL/6 J immune-competent hosts. Concurrent with this was a reduction in intra-tumoral infiltration of innate and adaptive immune cells, including macrophages and CD8(+) T cells. Evaluation of several potential mechanisms revealed an HSP70-chemokine-like activity to promote cellular migration. These observations support a role for tumor-derived HSP70 in facilitating anti-tumor immunity to limit tumor growth and highlight the potential consequences of anti-HSP70 therapy as an efficacious anti-cancer strategy.

• Authors: K Dodd, S Nance, M Quezada, L Janke, J B Morrison, R T Williams, H M Beere
• Journal: Oncogene (Oncogene) Vol. 34 Issue 10 Pg. 1312-22 (Mar 05 2015) ISSN: 1476-5594 [Electronic] England
• PMID: 24662819 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• HSP70 Heat-Shock Proteins
• Fusion Proteins, bcr-abl

Topics

• Animals
• Cell Line
• Cell Transformation, Neoplastic (genetics, metabolism)
• Disease Models, Animal
• Fusion Proteins, bcr-abl (genetics)
• Gene Expression
• Gene Knockdown Techniques
• Genes, myc
• HSP70 Heat-Shock Proteins (genetics, metabolism)
• Mice
• Mice, Knockout
• Neoplasms (genetics, immunology, metabolism, pathology)
• Oncogenes (genetics)
• Tumor Burden