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  • The earliest appearance of tumors

    2024-02-19

    The earliest appearance of tumors occurred at 12 months and the latest at 24 months, with an average onset at 18 months (Fig. 1B). This would be roughly equivalent to cancer presenting in a patient between 60 and 70 years of age. In transgenic animals, autotaxin mg115 was relatively increased in serum (*p < 0.05, Fig. 1C). Tumors appeared in disparate regions, including the mammary glands, chest cavity, liver, abdomen, uterus and head (Fig. 1D). Although many tumors could be classified, approximately 20% were unclassified and considered cancers of unknown primary origin. Histological analysis was unable to determine the characteristics indicative of a tissue of origin in these cases, although typical pathological features of central necrosis, large nuclei and diffuse carcinoma confirmed malignancy (Fig. 1E–H). Biofluids were collected at necropsy and RNA was isolated for serum microRNA PCR panels that probe the expression of 752 miRNAs in circulation (see Methods). GenEx qPCR Analysis Software (Exiqon/Qiagen) calculated the p-value significance of the data between groups versus the ratio of the effect size (Supplementary Fig. 2). Intriguingly, the autotaxin-mediated miRNome signature distinguished between wild-type FVB/N, AT-ATX tumor-bearing and AT-ATX non-tumor-bearing mice. Significant (*p < 0.05) increases in miRNA correlated with an autotaxin-mediated signature and clearly identified wild-type mice, but not necessarily the presence or absence of tumors in AT-ATX mice (Fig. 2A). Fold changes in miRNA expression comparing circulating miRNA in wild-type versus AT-ATX mice without tumors, further supported this observation, with increases up to 15-fold (Fig. 2B). Overall, patterns of circulating miRNA differentiated mice based on genotype status after hierarchical clustering algorithms computationally organized related groups with a miRNA signature (Fig. 2C). Analysis of the autotaxin-mediated miRNome signature through the DIANA TarBase database classified the miRNAs into various groups of oncogenic processes and signaling pathways. Autotaxin-dependent miRNAs show significant involvement in nearly all categories (Table 1). This suggests an impact of autotaxin on miRNA expression and its ‘high-risk’ influence on neoplastic disease. Subsequent aberrant miRNA regulation in signaling is a likely mechanism required for progression to a disease state, with the involvement of MAPK and other pathways. Comparing AT-ATX tumor-bearing versus non-tumor-bearing mice, miR-489-3p showed a significant (*p < 0.05) and consistent increase with autotaxin expression and subsequent tumor presence (Fig. 3A). The logarithmic scale differentiations were largely due to dramatic decreases in miRNA expression detected, with few exceptions, like miR-489-3p and miR-484 (Fig. 3B). Many significant miRNAs were decreased between AT-ATX tumor and non-tumor mice, with miR-30c-2-3p (p-value = 0.005) displaying the largest decrease, along with miR-192-3p (p-value = 0.0005) and miR-182-5p (p-value = 0.023). Interestingly, miR-489-3p showed an almost 4-fold increase in expression between the wild-type and non-tumor groups, and a further 6-fold increase with the presence of a tumor. Among AT-ATX mice that developed tumors, their pulverized tissues displayed generally more miR-489-3p than non-tumor AT-ATX mice (Fig. 3C, p = 0.03). Intriguingly, there was a correlation between the concentration of serum autotaxin with miR-489-3p expression in the tumor tissue and associated milieu (Fig. 3D, p = 0.0156). This suggests that with enhanced serum autotaxin concentration there is a coordinated displacement of miR-489-3p from cells to the milieu and serum (Fig. 3E). There was no relationship between the observed, primary, solid tumor volume with autotaxin concentration (data not shown). To determine whether changing miR-489-3p in mouse circulation has relevancy to human disease, we assessed human data. GSE106817 from Yokoi A. and colleagues contains over four-thousand serum samples from healthy, non-cancer controls (n = 2759) and patients with various cancers from nine major types (n = 1287). Circulating miR-489-3p was significantly increased among all cancer types (Supplementary Fig. 3, ***p < 0.001).