Abstract
There is an increasing number of studies showing that thrombocytosis—accompanying a variety of solid tumors including colorectal cancer (CRC)—is associated with shorter survival and earlier development of metastases. The mechanisms of cancer-associated thrombocytosis are not completely understood yet. The aim of our study was to evaluate the role of IL-6 in tumor development and thrombocytosis in mice with inflammation-induced CRC, using a CRISPR/cas9 IL-6 knockout (KO) strain. Adult male FB/Ant mice (n = 39) were divided into four groups: (1) IL-6 KO controls (n = 5); (2) IL-6 KO CRC model group (n = 18); (3) Wild-type (WT) controls (n = 6); and (4) WT CRC model group (n = 10). CRC model animals in (2) and (4) received azoxymethane (AOM)/dextran sodium sulfate (DSS) treatment to induce inflammation-related CRC. Plasma and liver tissues were obtained to determine platelet counts, IL-6 and thrombopoietin-1 (TPO) levels. In 1 WT and 2 IL-6 KO mice in vivo confocal endomicroscopy and 18F-fluorodeoxyglucose (FDG) PET/MRI examinations were performed to evaluate the inflammatory burden and neoplastic transformation. At the end of the study, tumorous foci could be observed macroscopically in both CRC model groups. Platelet counts were significantly elevated in the WT CRC group compared to the IL-6 KO CRC group. TPO levels moved parallelly with platelet counts. In vivo fluorescent microscopy showed signs of disordered and multi-nuclear crypt morphology with increased mucus production in a WT animal, while regular mucosal structure was prominent in the IL-6 KO animals. The WT animal presented more intense and larger colonic FDG uptake than IL-6 KO animals. Our study confirmed thrombocytosis accompanying inflammation-related CRC and the crucial role of IL-6 in this process. Significantly higher platelet counts were found in the WT CRC group compared to both the control group and the IL-6 KO group. Concomitantly, the tumor burden of WT mice was also greater than that of IL-6 KO mice. Our findings are in line with earlier paraneoplastic IL-6 effect suggestions.
Highlights
Colorectal cancer (CRC) is among the most prevalent malignancies worldwide
In the IL-6 KO group, IL-6 concentration did not increase after LPS administration, whereas WT animals showed a significant elevation of plasma IL-6 (Figure S1)
The mean TPO levels were similar in the control groups and the IL-6 KO CRC model group, the data range was greater in the latter group
Summary
Colorectal cancer (CRC) is among the most prevalent malignancies worldwide. With 1.65 million new cases and nearly 835 thousand deaths in the industrial world in 2015, CRC is the third most common form of neoplasia among males and the second most frequent one among females [1]. According to the hypothesis by Stone et al, tumors increase interleukin-6 (IL-6) levels which augments TPO production in the liver This in turn stimulates megakaryocytes in the bone marrow and eventually leads to thrombocytosis [15]. We decided to apply a widely used model of colitis-associated cancer (CAC) [16,17] whereby the cancer- inducing inflammatory stage is followed by progression of CRC. In this model, several interleukins including more prominently, IL-6 have been observed to drive progression and invasion [18,19]
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