Abstract
Cancer and cancer pain processes a major clinical challenge and the underlined mechanisms of pathogenesis remain elusive. We examined the specific changes in the transcriptomic profiles in the dorsal root ganglion (DRG) neurons of rats with bone cancer and bone cancer pain (BCP) using RNA sequencing technology. The bone cancer and BCP was induced by tumor cells implantation (TCI) into the tibia bone cavity in adult female rats. One week after treatment, TCI caused up- and down-regulation of thousands of genes in DRG. These genes were mainly involved in the immune process, inflammatory response, and intracellular signaling transduction of carbohydrate and cytokine. The cAMP and calcium signaling pathways were the major processes in the initial responses. Differentially expressed gene (DEG) analysis further showed that the genes for ion channels increased during day 1-7, while the genes for cytokine signaling pathways sustainedly increased during day 7-14 after TCI. The time courses of gene expression for ion channels and cytokines support their distinct roles in the early induction and late maintenance of BCP development. In addition, among the top 500 up- and down-regulated genes, 80-90% were unique for bone cancer pain as well as neuropathic and inflammatory pain, while less than 2% were shared among the three different forms of pain. This study reveals the uniqueness of mechanisms underlying bone cancer with pain, which is, to a large extent, differently from pain after acute inflammatory and nerve injury and provides novel potential targets of DEGs for bone cancer with pain.
Highlights
Bone cancer and bone cancer pain (BCP) continues to be a major clinical challenge
The patterns of gene expression alterations were highly synchronized with the development of BCP; (2) the cAMP and calcium signaling pathways are the major processes in the initial responses to the tumor cells implantation (TCI) treatment including initiation of induction of BCP, while cytokine signaling and other cell-defense related pathways mainly contribute to the subsequent development of BCP, in which cytokine receptor interaction (CCRI) may play the most important roles; (3) TCI treatment-induced Differentially expressed gene (DEG) of ion channels may contribute to the early induction of BCP, while cytokines contribute to the maintenance of BCP
None of the top 20 DEGs of ion channels in pain perception in literature is associated with cancer pain, most of the top 20 DEGs from CCRI pathway in pain perception is involved in cancer pain; and 4) among the top 500 up- and down-regulated genes, only less than 2% genes were shared among the different forms of pain produced by bone cancer, nerve injury, and acute inflammation, and most genes were unique, indicating the difference in pathogenesis of the different forms of pain
Summary
Bone cancer and bone cancer pain (BCP) continues to be a major clinical challenge. Despite decades of thorough study and continuous efforts, the underlined cellular and molecular mechanisms remain elusive and the clinical approaches for treating bone cancer and BCP are limited (van den Beukenvan Everdingen et al, 2007; Breivik et al, 2009). BCP happens in patients with primary bone sarcomas and predominantly occurs with distant metastases of non-bone cancer, including lung, breast, or prostate cancer (Kane et al, 2015). The incidence of BCP is estimated at around one-third of the patients with bone metastases (van den Beuken-van Everdingen et al, 2007; Scarborough and Smith, 2018). Cancer cells invade into tissue and induce nerve injury, indicating a neuropathic origination for cancer pain (Peters et al, 2005). The biochemical and microenvironmental changes further elicit sensitization and reconstruction of peripheral nerve endings and dorsal root ganglion (DRG) neurons that eventually result in pain
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