Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0279530 (bone cancer)
 1,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Emerging immune therapy, such as with the anti-programmed cell death-1 (anti-PD-1) monoclonal antibody nivolumab, has shown efficacy in tumor suppression. Patients with terminal cancer suffer from cancer pain as a result of bone metastasis and bone destruction, but how PD-1 blockade affects bone cancer pain remains unknown. Here, we report that mice lacking Pdcd1 (Pd1-/-) demonstrated remarkable protection against bone destruction induced by femoral inoculation of Lewis lung cancer cells. Compared with WT mice, Pd1-/- mice exhibited increased baseline pain sensitivity, but the development of bone cancer pain was compromised in Pd1-/- mice. Consistently, these beneficial effects in Pd1-/- mice were recapitulated by repeated i.v. applications of nivolumab in WT mice, even though nivolumab initially increased mechanical and thermal pain. Notably, PD-1 deficiency or nivolumab treatment inhibited osteoclastogenesis without altering tumor burden. PD-L1 and CCL2 are upregulated within the local tumor microenvironment, and PD-L1 promoted RANKL-induced osteoclastogenesis through JNK activation and CCL2 secretion. Bone cancer upregulated CCR2 in primary sensory neurons, and CCR2 antagonism effectively reduced bone cancer pain. Our findings suggest that, despite a transient increase in pain sensitivity following each treatment, anti-PD-1 immunotherapy could produce long-term benefits in preventing bone destruction and alleviating bone cancer pain by suppressing osteoclastogenesis.
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PMID:PD-1 blockade inhibits osteoclast formation and murine bone cancer pain. 3248 60

Herein, we summarize the steps of a common scientific path taken by the two Guest Editors, an Anesthesiologist (EA) and an Immunologist (AS), and started 25 years ago at the National Cancer Institute in Rome. When in 1980 WHO codified the usage of opioids for cancer pain relief, it was matter of debate whether only disease progression rather than opioid tolerance were the driving force of opioid escalation. The selective intratumoral accumulation of morphine observed in an experimental xenograft model - the initial scenario of our scientific collaboration - revealed a surprising interaction between the opioid and the opioid receptors expressed by cells of tumor microenvironment. This link could explain the peculiar opioid tolerance and likely hyperalgesia that were observed in the emerging clinical experience of cancer paradoxical pain and suggestive of opioid ambiguity. More elegant cancer pain experimental models, in particular of bone cancer, demonstrated the relevance of inflammatory mediators produced and released by tumor microenvironment cells. These factors were the words of an immune-mediated cross-talk between the tumor and the peripheral and central nervous systems leading to neuroinflammation and consequent pain hypersensitivity, chronicization of acute pain and maladaptive neuroplasticity. Immunology identified in the microglia activation a crucial hub of neuroinflammation and pain centralization. Subsequently the discovery of TLR-4 capacity to bind to opioids on glial cells revealed that they shared the same neuroinflammatory mechanisms underlying cancer and non cancer pain, and could also worsen pain for which they were used. The late awareness of this knowledge and the poor integration between immunological and pain sciences contributed to the recent severe opioid crisis in the USA (opioid epidemic) with a consequent limitation of long-term use of these drugs in non cancer pain, and generated a new wave of opiophobia. Immunological evidence-based pain therapies are currently quite sophisticated, but only little clinically exploited yet. To save the analgesic use of opioids would require the overcome of their intrinsic ability to cause both analgesia and hyperalgesia in a very ambiguous manner. At moment not to hijack and not to usurp the immune system appears still a very far goal.
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PMID:The ambiguity of opioids revealed by immunology is changing the knowledge and the therapeutic approach in cancer and non-cancer pain: A narrative review. 3259 Jan 20

Cancer pain, especially bone cancer pain, is a pain state often caused by inflammation or dysfunctional nerves. Moreover, in the management of cancer pain, opioid especially morphine is widely used, however, it also brings severe side effects such as morphine tolerance to the patient (Deandrea et al., 2008). A growing body of literatures demonstrated that neuroinflammation is mediated by microglia. As the macrophages like immune cells, microglia play an important role in the pathogenesis of cancer pain and morphine tolerance. Microglia acquire different activation states to regulate the function of these cells. As to M1 phenotype, microglia release pro-inflammatory cytokines and neurotoxic molecules that promote inflammation and cytotoxic reactions. Conversely, when microglia represent M2 phenotypes secreting anti-inflammatory cytokines and nutrient factors that promote the function of repair, regeneration and restore homeostasis. A better understanding of microglia activation in cancer pain and morphine tolerance is crucial for the development of hypothesized neuroprotective drugs. Targeting microglia different polarization states by the inhibition of their deleterious pro-inflammatory neurotoxicity and/or enhancing their beneficial anti-inflammatory protective function seems to be an effective treatment for cancer pain and morphine tolerance.
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PMID:The role of the M1/M2 microglia in the process from cancer pain to morphine tolerance. 3322 May 96


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