Abstract
The concentration of circulating heat shock protein 70 (Hsp70) was measured in liquid biopsies of canine tumor patients as a potential biomarker. Compared with rodent tumor models, spontaneously occurring tumors in pet dogs reflect the clinical situation of human patients better, as dogs cohabitate with their owners in the same environment, reach a much older age than rodents, can provide blood samples much more frequently, and receive up-to-date medical care and, similar to humans, their tumors show a high genetic heterogeneity. Due to the species-specific sequence homology of human and canine Hsp70, two human enzyme-linked immunosorbent assay (ELISA) systems (R&D and lipHsp70) were used to measure canine Hsp70 concentrations in serum and plasma. In general, higher Hsp70 concentrations were found in serum compared with plasma samples of dogs, and the lipHsp70 ELISA detected higher peak concentrations of Hsp70 in a broader range than the R&D ELISA. Compared with a tumor-free control group, serum Hsp70 concentrations were higher in tumor-bearing dogs, irrespective of breed, age, body weight, and gender. A sub-classification of the different tumors according to their cytological characteristics revealed significantly elevated Hsp70 serum concentrations in dogs with round cell tumors (p < 0.01), a heterogeneous group of malignancies with hematopoietic origin such as mast cells, plasma cells, lymphocytes, histiocytes, and melanomas. Future studies with larger patient cohorts and well-defined tumor sizes are necessary to elucidate the role of serum Hsp70 as a biomarker for tumor detection and monitoring of outcome in pet animals.
Highlights
Members of the different heat shock protein (HSP) families are highly conserved in evolution with a high sequenceMembers of the HSP70 family are found in most subcellular compartments, including the cytosol, nucleus, endoplasmic reticulum, mitochondria, lysosomes, and endosomes (Radons and Multhoff 2005)
By comparing heat shock protein 70 (Hsp70) levels of patients with tumors with an age- and gendermatched control cohort, we demonstrated that patients with tumors revealed significantly higher Hsp70 concentrations in the blood than healthy human volunteers
We addressed whether the lipHsp70 enzyme-linked immunosorbent assay (ELISA) could be used to detect Hsp70 in the serum and plasma of pet dogs with spontaneous tumors
Summary
Members of the different heat shock protein (HSP) families are highly conserved in evolution with a high sequenceMembers of the HSP70 family are found in most subcellular compartments, including the cytosol, nucleus, endoplasmic reticulum, mitochondria, lysosomes, and endosomes (Radons and Multhoff 2005). Free Hsp originating from dying cells and exosomal Hsp which is actively released by viable tumor cells can be quantified in the blood of patients with tumors by using the novel lipHsp ELISA (Breuninger et al 2014). This ELISA is based on the cmHsp70.1 mouse IgG1 monoclonal antibody (mAb) detecting an 8-mer epitope of Hsp in the C-terminal oligomerization domain that is exposed on the surface of tumor cells and tumor-derived exosomes (Stangl et al 2011; Breuninger et al 2014). Elevated Hsp serum and plasma levels could be correlated with the viable tumor mass in patients with non-small cell lung carcinoma (NSCLC) before and after radiochemotherapy (Gunther et al 2015)
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