Abstract
BackgroundMetastatic cancer to bone is well-known to produce extreme pain. It has been suggested that the magnitude of this perceived pain is associated with disease progression and poor prognosis. These data suggest a potential cross-talk between cancer cells and nociceptors that contribute not only to pain, but also to cancer aggressiveness although the underlying mechanisms are yet to be stablished.MethodsThe in vitro dose dependent effect of neuropeptides (NPs) (substance P [SP], calcitonin gene-related peptide and neurokinin A [NKA]) and/or its combination, on the migration and invasion of MDA-MB-231LUC+ were assessed by wound healing and collagen-based cell invasion assays, respectively. The effect of NPs on the expression of its receptors (SP [NK1] and neurokinin A receptors [NK2], CALCRL and RAMP1) and kininogen (high-molecular-weight kininogen) release to the cell culture supernatant of MDA-MB-231LUC+, were measured using western-blot analysis and an ELISA assay, respectively. Statistical significance was tested using one-way ANOVA, repeated measures ANOVA, or the paired t-test. Post-hoc testing was performed with correction for multiple comparisons as appropriate.ResultsOur data show that NPs strongly modify the chemokinetic capabilities of a cellular line commonly used as a model of metastatic cancer to bone (MDA-MB-231LUC+) and increased the expression of their receptors (NK1R, NK2R, RAMP1, and CALCRL) on these cells. Finally, we demonstrate that NPs also trigger the acute release of HMWK (Bradykinin precursor) by MDA-MB-231LUC+, a molecule with both tumorigenic and pro-nociceptive activity.ConclusionsBased on these observations we conclude that NPs exposure modulates this breast cancer cellular line aggressiveness by increasing its ability to migrate and invade new tissues. Furthermore, these results also support the pro nociceptive and cancer promoter role of the peripheral nervous system, during the initial stages of the disease.
Highlights
Metastatic cancer to bone is well-known to produce extreme pain
Afferents to signal pain and the antidromic release of their bioactive contents into surrounding tissues [8]. This neuro-inflammatory process includes the release of several neuropeptides (NPs), calcitonin gene-related peptide [CGRP] and neurokinin A [NKA]) well recognized for their pro-tumorigenic functions via paracrine and autocrine loops [9,10,11,12,13]
Afterwards, the insert was removed, and cells were allowed to migrate in FBS free media containing vehicle, 1, 10, 100 and 1000 nM of SP, CGRP or NKA or 100 nM of SP, 100 nM of CGRP, 50 nM of NKA or their combination
Summary
Metastatic cancer to bone is well-known to produce extreme pain. It has been suggested that the magnitude of this perceived pain is associated with disease progression and poor prognosis. Pain with early bone metastasis cannot be explained by tissue damage or the magnitude of the inflammatory process, indicating a neuropathic nature [2,3,4,5,6,7] Important to this process are the orthodromic activation of nociceptive sensory afferents to signal pain (peripheral pain sensors) and the antidromic release of their bioactive contents into surrounding tissues (neurogenic inflammation) [8]. This neuro-inflammatory process includes the release of several neuropeptides (NPs) (substance P [SP]), calcitonin gene-related peptide [CGRP] and neurokinin A [NKA]) well recognized for their pro-tumorigenic functions via paracrine and autocrine loops [9,10,11,12,13].
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