Human C1q Tumor Necrosis Factor 8 (CTRP8) defines a novel tryptase+ mast cell subpopulation in the prostate cancer microenvironment

Sai Nivedita Krishnan; Thatchawan Thanasupawat; Leanne Arreza; G William Wong; Karen Sfanos; Bruce Trock; Michel Arock; G Girish Shah; Aleksandra Glogowska; Saeid Ghavami; Sabine Hombach-Klonisch; Thomas Klonisch

doi:10.1016/j.bbadis.2023.166681

Human C1q Tumor Necrosis Factor 8 (CTRP8) defines a novel tryptase+ mast cell subpopulation in the prostate cancer microenvironment

Biochim Biophys Acta Mol Basis Dis. 2023 Jun;1869(5):166681. doi: 10.1016/j.bbadis.2023.166681. Epub 2023 Mar 13.

Affiliations

¹ Dept. of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Canada.
² Dept. of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
³ Dept. of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁴ Dept. of Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁵ Laboratoire d'Hématologie Biologique, Hôpital Pitié-Salpêtrière, Paris, France.
⁶ Dept. of Molecular Biology, Medical Biochemistry and Pathology, Faculty of Medicine, CHU de Quebec-Laval, Quebec, Canada.
⁷ Dept. of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Canada; Research Institute of Cancer and Hematology, CancerCare Manitoba, Canada; Children's Hospital Research Institute of Manitoba, Winnipeg, Manitoba, Canada.
⁸ Dept. of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Canada; Dept. of Pathology, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Canada; Children's Hospital Research Institute of Manitoba, Winnipeg, Manitoba, Canada. Electronic address: sabine.hombach-klonisch@umanitoba.ca.
⁹ Dept. of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Canada; Dept. of Pathology, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Canada; Research Institute of Cancer and Hematology, CancerCare Manitoba, Canada; Children's Hospital Research Institute of Manitoba, Winnipeg, Manitoba, Canada; Dept. of Medical Microbiology & Infectious Diseases, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Canada. Electronic address: thomas.klonisch@umanitoba.ca.

PMID: 36921737
DOI: 10.1016/j.bbadis.2023.166681

Abstract

The adipokine C1q Tumor Necrosis Factor 8 (CTRP8) is the least known member of the 15 CTRP proteins and a ligand of the relaxin receptor RXFP1. We previously demonstrated the ability of the CTRP8-RXFP1 interaction to promote motility, matrix invasion, and drug resistance. The lack of specific tools to detect CTRP8 protein severely limits our knowledge on CTRP8 biological functions in normal and tumor tissues. Here, we have generated and characterized the first specific antiserum to human CTRP8 which identified CTRP8 as a novel marker of tryptase+ mast cells (MC_T) in normal human tissues and in the prostate cancer (PC) microenvironment. Using human PC tissue microarrays composed of neoplastic and corresponding tumor-adjacent prostate tissues, we have identified a significantly higher number of CTRP8+ MC_T in the peritumor versus intratumor compartment of PC tissues of Gleason scores 6 and 7. Higher numbers of CTRP8+ MC_T correlated with the clinical parameter of biochemical recurrence. We showed that the human MC line ROSA^{KIT WT} expressed RXFP1 transcripts and responded to CTRP8 treatment with a small but significant increase in cell proliferation. Like the cognate RXFP1 ligand RLN-2 and the small molecule RXFP1 agonist ML-290, CTRP8 reduced degranulation of ROSA^{KIT WT} MC stimulated by the Ca²⁺-ionophore A14187. In conclusion, this is the first report to identify the RXFP1 agonist CTRP8 as a novel marker of MC_T and autocrine/paracrine oncogenic factor within the PC microenvironment.

Keywords: C1QTNF8; CTRP8; Mast cells; Prostate cancer; ROSAKIT WT cells; RXFP1; Tryptase.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Complement C1q*
Humans
Ligands
Male
Mast Cells
Prostate
Prostatic Neoplasms* / genetics
Tryptases
Tumor Microenvironment
Tumor Necrosis Factors

Substances

Complement C1q
Ligands
Tryptases
Tumor Necrosis Factors
C1QTNF8 protein, human