Exosome-associated lysophosphatidic acid signaling contributes to cancer pain

Abstract

Pain associated with bone cancer remains poorly managed, and chemotherapeutic drugs used to treat cancer usually increase pain. The discovery of dual-acting drugs that reduce cancer and produce analgesia is an optimal approach. The mechanisms underlying bone cancer pain involve interactions between cancer cells and nociceptive neurons. We demonstrated that fibrosarcoma cells express high levels of autotaxin (ATX), the enzyme synthetizing lysophosphatidic acid (LPA). Lysophosphatidic acid increased proliferation of fibrosarcoma cells in vitro. Lysophosphatidic acid is also a pain-signaling molecule, which activates LPA receptors (LPARs) located on nociceptive neurons and satellite cells in dorsal root ganglia. We therefore investigated the contribution of the ATX–LPA–LPAR signaling to pain in a mouse model of bone cancer pain in which fibrosarcoma cells are implanted into and around the calcaneus bone, resulting in tumor growth and hypersensitivity. LPA was elevated in serum of tumor-bearing mice, and blockade of ATX or LPAR reduced tumor-evoked hypersensitivity. Because cancer cell–secreted exosomes contribute to hypersensitivity and ATX is bound to exosomes, we determined the role of exosome-associated ATX–LPA–LPAR signaling in hypersensitivity produced by cancer exosomes. Intraplantar injection of cancer exosomes into naive mice produced hypersensitivity by sensitizing C-fiber nociceptors. Inhibition of ATX or blockade of LPAR attenuated cancer exosome-evoked hypersensitivity in an ATX–LPA–LPAR-dependent manner. Parallel in vitro studies revealed the involvement of ATX–LPA–LPAR signaling in direct sensitization of dorsal root ganglion neurons by cancer exosomes. Thus, our study identified a cancer exosome-mediated pathway, which may represent a therapeutic target for treating tumor growth and pain in patients with bone cancer.

The Emerging Role of LPA as an Oncometabolite

“…Interestingly, isolation stress triggers the expression of LPAR4 to promote the adaptation of cancer cells to stress and subsequently promote survival [148,149]. The role of LPA in cancer-related pain is showcased in fibrosarcoma, where exosomal LPA through LPARs induces cancerrelated pain by sensitising C-fibre nociceptors [150]. LPA also affects senescence, as in hepatocellular carcinoma, LPA activates LPAR1, which interacts with myocardin-related transcription factor A (MRTF-A) and filamin A to trigger actin polymerisation and protect against oncogene-induced senescence [151].…”

Membranes on the move: The functional role of the extracellular vesicle membrane for contact‐dependent cellular signalling

“…However, it is difficult to discriminate if these vesicles are in the process of cellular attachment and up to be endocytosed or if they have just been released from the cell. However, they demonstrate that EVs are deformable particles and that a planar interaction interface between the EV and the cell membrane can be formed (Bigagli et al., 2016 ; Edgar et al., 2016 ; Khasabova et al., 2023 ; Salas et al., 2021 ). Given that a single EV could engage in 5–50 ligand–receptor interactions on a cell membrane with a typical binding energy of approximately 10 kJ/mol per receptor (which equals 4 k B T at room temperature) and assuming a membrane bending rigidity close to synthetic lipid membranes of 20–30 k B T (Faizi et al., 2022 ), already a few ligand‐receptor interactions can be sufficient to induce EV deformation.…”

Autotaxin as a novel biomarker of migraine

“…LPA exerts its function through speci c membrane receptors (LPARs), involved in several mechanisms, such as platelets aggregation, vascular tone control, in ammation, endothelial dysfunction, and neuropathic pain; among others [12][13][14]. As mentioned, the ATX-LPA axis has been described to modulate different processes that are involved in the development and evolution of migraines, such as vascular tone [15,16], in ammation [17,18], neuroin ammation [19], and neuronal excitation [20], and pain [21,22]. However, its implication in migraine has not been studied.…”