Abstract
Multiple myeloma is one of the most common hematological diseases and is characterized by an aberrant proliferation of plasma cells within the bone marrow. As a result of crosstalk between cancer cells and the bone microenvironment, bone homeostasis is disrupted leading to osteolytic lesions and poor prognosis. Current diagnostic strategies for myeloma typically rely on detection of excess monoclonal immunoglobulins or light chains in the urine or serum. However, these strategies fail to localize the sites of malignancies. In this study we sought to identify novel biomarkers of myeloma bone disease which could target the malignant cells and/or the surrounding cells of the tumor microenvironment. From these studies, the KISS1 receptor (KISS1R), a G-protein-coupled receptor known to play a role in the regulation of endocrine functions, was identified as a target gene that was upregulated on mesenchymal stem cells (MSCs) and osteoprogenitor cells (OPCs) when co-cultured with myeloma cells. To determine the potential of this receptor as a biomarker, in vitro and in vivo studies were performed with the KISS1R ligand, kisspeptin, conjugated with a fluorescent dye. In vitro microscopy showed binding of fluorescently-labeled kisspeptin to both myeloma cells as well as MSCs under direct co-culture conditions. Next, conjugated kisspeptin was injected into immune-competent mice containing myeloma bone lesions. Tumor-burdened limbs showed increased peak fluorescence compared to contralateral controls. These data suggest the utility of the KISS1R as a novel biomarker for multiple myeloma, capable of targeting both tumor cells and host cells of the tumor microenvironment.
Highlights
Multiple myeloma (MM) is one of the most common forms of hematological diseases, accounting for 10% of hematological cancers and 1% of all malignant tumors [1, 2]
The aim of this study was to test whether KISS1 receptor (KISS1R) and kisspeptin are expressed in MM cells and cells of the tumor microenvironment, whether interactions between MM cells and skeletal precursors resulted in up-regulation of the KISS1R-kisspeptin system, and whether these changes in gene expression signature could be used as a tool to develop a novel biomarker for the MM microenvironment in myeloma bone disease suitable for diagnostics and therapy
KISS1R expressed in skeletal precursor cells was found to be of a greater molecular weight than that expressed in the MM cell line INA-6, as well as in the breast cancer cell line MCF-7 (Fig 1C) previously characterized to express high levels of the KISS1R [33]
Summary
Multiple myeloma (MM) is one of the most common forms of hematological diseases, accounting for 10% of hematological cancers and 1% of all malignant tumors [1, 2]. Skeletal lesions are the result of a tight interaction between, among others, MM and mesenchymal stem cells (MSCs) and other skeletal precursors of the bone marrow microenvironment, which deliver pro-survival signals and promote MM progression and chemo-resistance [3,4,5,6,7]. These signals are mediated by direct cell-cell contact via e.g. integrin receptors [8], by cytokines such as interleukin-6 (IL-6), hepatocyte, vascular and insulin-like growth factors and by transforming growth factor-beta, all derived from the bone marrow microenvironment. Because of the prominent role the bone marrow cells play in MM progression, identifying new molecules specific for the MM microenvironment would prove valuable for both diagnostic and therapeutic targeting
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