Neuropeptide-induced modulation of carcinogenesis in a metastatic breast cancer cell line (MDA-MB-231LUC+)

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.

The Neurokinin-1 Receptor Antagonist Aprepitant, a New Drug for the Treatment of Hematological Malignancies: Focus on Acute Myeloid Leukemia

“…Thus, in a patient treated with radiotherapy and a NK-1R antagonist (aprepitant, 1140 mg/day for 45 days), the tumor mass disappeared after six months and no serious side-effects were observed [50], and in patients with cancer, the efficacy (promoting apoptosis) of targeted alpha therapy with 213 Bi-DOTA-SP (radionuclide tumor therapy) against tumor cells has been reported [51][52][53][54][55]. Another important finding is that SP, in cancer cells, augmented the expression of the NK-1R, but not that of other receptors (e.g., NK-2R) [56]. This finding is crucial because SP, in addition to promoting mitogenesis/migration of cancer cells as well as an anti-apoptotic effect (that is exerting beneficial actions in tumor cells), increases the expression of the NK-1R, which is overexpressed in cancer cells.…”

“…Why is the NK-1R essential for cancer cells? As tumor cells need the beneficial SP stimulus (which induces cell proliferation and migration, an anti-apoptotic effect and increases the synthesis of the NK-1R), they overexpress the NK-1R [13,18,27,56]. When the NK-1R expression is silenced, or NK-1R antagonists are administered (which leads to the blockade of the SP stimulus), tumor cells develop apoptotic mechanisms ( Figure 1).…”

Profiling of how nociceptor neurons detect danger – new and old foes

“…In support of such a function, oesophageal, colorectal cancer , breast cancer and cardiac carcinoma were also found to promote neuritogenesis in vitro . More precisely, it was determined that VEGFα released by breast cancer carcinoma drives neuritogenesis, whilst neuropeptides released by sensory neurons enhance chemokinesis . Besides VEGFα, cancer cells released NGF and neurturin can also trigger neurite outgrowth.…”

The Neurokinin-1 Receptor Antagonist Aprepitant, a New Drug for the Treatment of Hematological Malignancies: Focus on Acute Myeloid Leukemia

“…but not that of other receptors (e.g., NK-2R) [58]. This finding is crucial because SP, in addition to promote mitogenesis/migration of cancer cells as well as an anti-apoptotic effect (that is exerting beneficial actions in tumor cells), the undecapeptide increases the expression of the NK-1R which is overexpressed in cancer cells.…”

“…Why is the NK-1R essential for cancer cells? As tumor cells need the beneficial SP stimulus (which induces cell proliferation and migration, an anti-apoptotic effect and increases the synthesis of the NK-1R) they overexpress the NK-1R [15,20,29,58]. When the NK-1R expression is silenced, or NK-1R antagonists are administered (which leads to the blockade of the SP stimulus), tumor cells develop apoptotic mechanisms.…”