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The structure and dynamics of the neurokinin (NK)-2, NK-3, and calcitonin gene-related peptide (CGRP) receptors are studied together with the intracellular signaling pathways in which they are involved. These peptides play an important role in many cancers, such as breast cancer, colorectal cancer, glioma, lung cancer, neuroblastoma, oral squamous cell carcinoma, phaeochromocytoma, leukemia, bladder cancer, endometrial cancer, Ewing sarcoma, gastric cancer, liver cancer, melanoma, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, renal carcinoma, and thyroid cancer. These peptides are involved in tumor cell proliferation, migration, metastasis, angiogenesis, and lymphangiogenesis.
Small bowel neuroendocrine tumors are difficult to diagnose; thus, it is important to determine specific biomarkers associated with the disease. NKA is a specific blood biomarker because high plasma NKA levels (≥50 ng/L) have been associated with poor prognosis in patients with these tumors. Monitoring such levels could be useful in selecting patients with a poor prognosis; hence, a high NKA level means that an urgent therapeutic intervention is needed [122][123][124][125][126].
Compared with healthy individuals, a rise in circulating NKA/SP has been reported in patients suffering from ileal metastatic carcinoid tumors showing cutaneous flushing; the release of both peptides from carcinoid tumors was partially blocked after the administration of a somatostatin analog [127]. The presence of NKA, NKA3-10, and NKA4-10 has been detected in ileal metastatic carcinoid tumors [128].
Tumor | AM/AM2/AMY/CGRP | References |
---|---|---|
Acute myeloid leukemia | AM, CLR, RAMP 2/3 expression. A high AM level is associated with low overall survival/disease-free survival. AM/AM22–52 regulates cell growth. AM expression associated with genes related to immunosuppression resistance. AM correlates with adverse outcomes. Targeting calcitonin receptor-like receptors prevents relapse. Calcitonin gene methylation pattern: independent prognostic factor. High calcitonin receptor expression: poor prognosis and correlates with chemotherapy resistance. Olcegepant decreases leukemic burden/stem cell characteristics. MK0974 promotes apoptosis. |
[139][140][141][142][143][144] |
Adrenocortical tumor | AM is synthesized/released from adrenocortical tumors and phaeochromocytomas. Phaeochromocytomas: higher AM/receptor mRNA expression. Phaeochromocytomas and adenomas: AM2 expression. AM blocks phaeochromocytoma cell proliferation. AM level as a biomarker. Adrenal tumors: AM2, CLR, RAMP1/RAMP2/RAMP3 mRNA expression. Phaeochromocytomas: high CGRP tissue level. |
[145][146][147][148][149][150] |
Bladder cancer | High AM level. AM knockdown promotes apoptosis. AM knockdown/cisplatin combination decreases tumor growth. |
[151] |
Breast cancer | AM expression associated with axillary lymph node metastasis. RAMP3: involved in metastasis. Tumor cells overexpressing AM: potential angiogenic increase/less apoptotic mechanisms. Tumor cells expressing/releasing AM: favor cell proliferation, breast cancer bone metastasis, and angiogenesis. AM is a tumor survival factor. Triple-negative breast cancer samples: AM expression decreased; this low expression is related to poor prognosis and increased risk of recurrence/metastasis. AM22–52 disrupts tumor vasculature, decreases tumor cell proliferation, and induces apoptosis. Plasma AM2 level associated with poor patient outcomes. AM2 expression increased: correlated with Ki67 expression/lymph node metastasis. AM2 promotes cancer cells’ growth, migration, and invasion; these actions were blocked with anti-AM2 antibodies. CGRP expression increased. CGRP is involved in metastasis. |
[74][152][153][154][155][156][157][158][159] |
Choriocarcinoma | AM mRNA expression. | [160] |
Colon cancer | CLR and RAMP2/3 expressions. High levels of AM, CLR, and RAMP2/3 are correlated with lymph nodes and distant metastasis. High AM level is related to low disease-free survival. Higher AM level and AM mRNA expression. AM promotes tumor cell proliferation/invasion and antiapoptotic effect. AM level associated with clinical survival rate/cancer stage. Knockdown AM promotes apoptosis/blocks angiogenesis. AM expression is associated with vascular endothelial growth factor and hypoxia-inducible factor-1α. AM positive modulator (145425) decreases the number of tumors. Higher mRNA pre-proAM, pre-proAM2, CLR, RAMP2/3, MMP-9, and VEGF-A expression. Positive correlation between MMP-9 gene expression and pre-proAM, but not pre-proAM2. |
[137][161][162][163][164][165][166] |
Cutaneous nerve neuromas | Saphenous nerve neuromas: CGRP release from nerve fibers. | [167] |
Endometrial cancer | AM favors angiogenesis/tumor growth and blocks tumor cell death. AM level increases from normal, simple, or complex hyperplasia with or without atypia to grade 1 adenocarcinoma. |
[76][168][169][170] |
Ewing sarcoma | CGRP expression. CGRP promotes the proliferation of cancer cells. |
[171] |
Gastric cancer | Tumor-derived AM promotes mast cell degranulation, as well as favors tumor cell proliferation, and the apoptosis blockade in cancer cells. | [172] |
Glioma | AM favors mitogenesis in tumor cells and exerts angiogenic/antiapoptotic effects. AM mRNA is associated with tumor type and grade. c-Jun/JNK pathway is involved in the growth regulatory activity mediated by AM. AM expression is upregulated in temozolomide-resistant glioma samples: miR-1297 targets AM, blocks its expression, and sensitizes tumor cells to temozolomide treatment. AM2 expression is increased and correlated with higher-grade gliomas. AM2 increases the invasive capacity of tumor cells and improves tumor blood. AMY promotes the release of inflammatory cytokines from tumor cells. The signal transducer and STAT-3 in astroglioma control AM expression. AM promotes the migration of astroglioma cells. |
[173][174][175][176][177][178][179][180][181] |
Head and neck squamous cell carcinoma | Peripheral nerve terminals release CGRP, which exerts a paracrine action on tumor cells. CGRP links perineural invasion and lymph node metastasis. Pre-operative plasma CGRP level: lymph node metastasis predictor. |
[182][183] |
Liver cancer | CLR and RAMP2/3 expression. High AM level is related to increased intrahepatic metastasis. Higher AM mRNA levels in tumor tissues than in adjacent nontumor tissues. AM mediates the epithelial–mesenchymal transition and promotes tumor cell growth. Knockdown AM expression promotes apoptotic mechanisms and, combined with cisplatin, decreases tumor growth. Microvessel density and mRNA AM/erythropoietin receptor levels are higher in hepatocellular carcinoma than in nontumor tissues: both levels are correlated with tumor metastasis, pathological differentiation, and capsule invasion. AM is associated with N-cadherin intensity, vascular invasion, and poor prognosis. AM level as a prognostic factor. High AM2 mRNA expression even in early stages. AM2 increases tumor cell proliferation and survival, and is involved in angiogenesis: AM217–47 blocked this proliferation. AMY binding site expression. |
[184][185][186][187][188][189][190][191][192] |
Lung cancer | AM expression does not correlate with survival, cancer stage, or tumor differentiation. AM contributes to the carcinogenicity of tobacco-activated aryl hydrocarbon receptor products. CGRP gene expression. |
[193][194][195][196] |
Melanoma | Tumor-associated macrophages, through AM, favor melanoma growth and angiogenesis. The number of tumor-associated macrophages (express/release AM) in the tumor microenvironment is correlated with poor prognosis. Tumor-associated macrophages favor the migration of endothelial cells and increase tumor cell growth. |
[197] |
Nasopharyngeal carcinoma | AM level as a biomarker for predicting prognosis. | [198] |
Neuroblastoma | AM receptor expression. AM mRNA expression is associated with tumor differentiation. |
[199][200] |
Neuroendocrine tumors | High plasma and tissue AM expression: predictive factors for tumor progression and worsened prognosis. | [201] |
Oropharyngeal squamous cell carcinoma | Jumonji domain-containing 1A, H3K9me1/2, and AM expression: predictor markers for progression and prognosis. JMJD1A gene target AM favors tumorigenesis/cell growth. | [202] |
Osteosarcoma | AM expression is associated with metastasis degree/malignancy. AM overexpression. AM exerts an antiapoptotic effect. |
[203][204] |
Ovarian cancer | High AM level is related to tumor stage. AM gene is correlated with histological grade, lymph node metastasis, and prognosis but not with disease stage, histological subtype, residual tumor mass after initial surgery, and patient’s age at diagnosis. Tumor cells express AM mRNA for both ligand/receptor. AM is involved in tumor progression/cell migration. AM gene silencing blocks cell proliferation and increases tumor cell chemosensitivity. Cancer patients with high AM expression show larger residual size of tumors, shorter disease-free/overall survival time, and higher metastasis incidence. AM as biomarker to evaluate prognosis/malignant potential. AM is correlated with expressions of HIF-1α, VEGF, or microvessel density. AM favors angiogenesis. |
[205][206][207][208][209][210] |
Pancreatic cancer | High AM levels are associated with disease-free survival decrease. Higher AM plasma level. AM level is higher in cancer patients with diabetes than those without diabetes. Insulinoma: circulating AM increased. AM and its receptor are expressed. AM is involved in tumor cell proliferation, migration, invasion, metastasis, and angiogenesis. AM mRNA/protein expressions are increased. AM as a tumor marker. AM receptor silencing blocks AM-induced cell growth and invasion. AM antagonists decrease tumor cell growth/blood vessel diameter. Selective RAMP2 activation/RAMP3 inhibition: tumor metastasis suppression. AM2 as tumor angiogenic factor. AM2 level: poorer survival predictor. AM2 is a biomarker predicting survival. Insulinomas express AMY. Plasma AMY levels are increased in nondiabetic patients with cancer; this level is low in patients with diabetes. CALCA (αCGRP) and CALCB (βCGRP) methylation increases. |
[211][212][213][214][215][216][217][218][219][220][221][222] |
Pituitary adenoma | AM expression is decreased in anterior pituitary tumors. | [223] |
Prostate cancer | AM is expressed in prostate carcinomas. A high AM level is associated with a high Gleason score. Plasma AM2 level is associated with Gleason’s score, tumor node metastasis, and 5 year metastasis. AM overexpression inhibits tumor cell growth and dysregulates genes involved in apoptosis, cell cycle, extracellular matrix, cell adhesion, and cytoskeleton. AM promotes human prostate growth via the AM2 receptor (CLR/RAMP3) subtype. AM blocks apoptosis in specific tumor cells. AM, upon androgen ablation, is involved in hormone-independent tumor growth, lymphangiogenesis, and neoangiogenesis. AM promotes cancer cell migration and invasion. AM2 is involved in cancer cell migration/angiogenesis. Higher plasma AM2 level in patients with prostate cancer. Patients with a Gleason score ≥7, unconfined organ, seminal vesicle invasion, tumor node metastasis stage T2, positive lymph node, or extra-prostatic extension show high AM2. AM2 as a prognostic, predictive biomarker for 5 year metastasis and 5 year progression. CGRP increases the invasive/migratory capacity of tumor cells. CGRP serum level correlates with cancer progression. Higher serum CGRP level is associated with higher histological grade/clinical stages. CGRP receptor mediates metastasis. CGRP promotes tumor growth which is blocked with CGRP antagonists. |
[138][224][225][226][227][228][229][230][231][232][233] |
Renal carcinoma | AM, CLR, and RAMP2/3 expression. High CLR level is associated with high tumor grade. AM and AM mRNA expression. AM mRNA expression is correlated with VEGF-A mRNA. AM, via CLR/RAMP2 and CLR/RAMP3 receptors, promotes cell proliferation, migration, and invasion. High AM mRNA level is related to increased risk of relapse. |
[234][235][236] |
Thymic lymphomas | Pramlintide promotes tumor regression. AMY blocks glycolysis, promotes reactive oxygen species formation, and induces apoptosis. |
[237] |
Thyroid cancer | AM2 expression is increased in obese patients with thyroid cancer, showing locoregional recurrence, a high prevalence of lymph node metastasis, and larger tumor size. High circulating AM2/tumor cell AM2 expression levels are associated with aggressive pathological parameters. AM2 as a biomarker for predicting thyroid tumor progression. Medullary thyroid carcinoma: high AMY levels. Plasma AMY/insulin levels are correlated in medullary thyroid carcinoma. CGRP gene expression. Plasma CGRP level marker for medullary thyroid carcinoma. |
[195][238][239][240][241] |
Uterine cervical carcinoma | High AM and AM mRNA expression. AM is involved in promoting malignant progression and in selecting carcinoma cells resistant to apoptosis. |
[242][243] |