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BACKGROUND: The Ec peptide (PEc) that defines the IGF-1Ec isoform, is associated with prostate cancer progression by inducing proliferation, metastases, and tumour repair. On these grounds, an anti-PEc monoclonal antibody (MAb) was developed. Our objective is to examine the effects of this antibody on prostate cancer and its possible side effects. METHODS: The effects of the obtained MAb were examined in cancer and non-cancerous cell lines (unmodified and modified either to overexpress or silence PEc) and in tumours in SCID mice injected with unmodified prostate cancer cells. The investigation was obtained with respect to cellular proliferation, migration, invasion, toxicity to tumours, effects on the cell cycle, immune response activation, effects on mesenchymal stem cell mobilisation leading to tumour repair, tissue distribution, and toxicity to mice. RESULTS: Anti-PEc MAb treatment led to a significant decrease in cellular proliferation, migration, and invasion compared to the untreated cell lines (p < 0.0005 in every case). Mechanistically, these effects were associated with the downregulation of pERK1/2 and vimentin and the upregulation of E-Cadherin. In vivo, anti-PEc MAb treatment was associated with a significant decrease in tumour size and metastases rate (p < 0.0005 in every case) by reversing the tumours mesenchymal phenotype. It also inhibited host stem cell mobilisation towards the tumour, leading to apoptosis. Anti-PEc MAb assessment in respect to distribution and toxicity, indicated its tumour specificity and lack of toxicity. CONCLUSIONS: These data indicate that the therapeutic targeting of PEc with the anti-PEc MAb may have considerable clinical benefit for prostate cancer patients.
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Anticorpos Monoclonais , Proliferação de Células , Camundongos SCID , Neoplasias da Próstata , Masculino , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/tratamento farmacológico , Animais , Humanos , Camundongos , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Fator de Crescimento Insulin-Like I/imunologiaRESUMO
This review offers a comprehensive exploration of the intricate immunological landscape of breast cancer (BC), focusing on recent advances in diagnosis and prognosis through the analysis of circulating tumor cells (CTCs). Positioned within the broader context of BC research, it underscores the pivotal role of the immune system in shaping the disease's progression. The primary objective of this investigation is to synthesize current knowledge on the immunological aspects of BC, with a particular emphasis on the diagnostic and prognostic potential offered by CTCs. This review adopts a thorough examination of the relevant literature, incorporating recent breakthroughs in the field. The methodology section succinctly outlines the approach, with a specific focus on CTC analysis and its implications for BC diagnosis and prognosis. Through this review, insights into the dynamic interplay between the immune system and BC are highlighted, with a specific emphasis on the role of CTCs in advancing diagnostic methodologies and refining prognostic assessments. Furthermore, this review presents objective and substantiated results, contributing to a deeper understanding of the immunological complexity in BC. In conclusion, this investigation underscores the significance of exploring the immunological profile of BC patients, providing valuable insights into novel advances in diagnosis and prognosis through the utilization of CTCs. The objective presentation of findings emphasizes the crucial role of the immune system in BC dynamics, thereby opening avenues for enhanced clinical management strategies.
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Biomarcadores Tumorais , Neoplasias da Mama , Células Neoplásicas Circulantes , Humanos , Células Neoplásicas Circulantes/imunologia , Células Neoplásicas Circulantes/patologia , Células Neoplásicas Circulantes/metabolismo , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/imunologia , Neoplasias da Mama/sangue , Prognóstico , FemininoRESUMO
Breast cancer (BC), one of the most widespread and devastating diseases affecting women worldwide, presents a significant public health challenge. This review explores the emerging frontiers of research focused on deciphering the intricate interplay between BC cells and the immune microenvironment. Understanding the role of the immune system in BC is critical as it holds promise for novel therapeutic approaches and precision medicine strategies. This review delves into the current literature regarding the immune microenvironment's contribution to BC initiation, progression, and metastasis. It examines the complex mechanisms by which BC cells interact with various immune cell populations, including tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs). Furthermore, this review highlights the impact of immune-related factors, such as cytokines and immune checkpoint molecules. Additionally, this comprehensive analysis sheds light on the potential biomarkers associated with the immune response in BC, enabling early diagnosis and prognostic assessment. The therapeutic implications of targeting the immune microenvironment are also explored, encompassing immunotherapeutic strategies and combination therapies to enhance treatment efficacy. The significance of this review lies in its potential to pave the way for novel therapeutic interventions, providing clinicians and researchers with essential knowledge to design targeted and personalized treatment regimens for BC patients.
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Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/patologia , Linfócitos do Interstício Tumoral , Terapia Combinada , Citocinas , Microambiente Tumoral , ImunoterapiaRESUMO
According to the WHO's recently released worldwide cancer data for 2020, liver cancer ranks sixth in morbidity and third in mortality among all malignancies. Hepatocellular carcinoma (HCC), the most common kind of liver cancer, accounts approximately for 80% of all primary liver malignancies and is one of the leading causes of death globally. The intractable tumor microenvironment plays an important role in the development and progression of HCC and is one of three major unresolved issues in clinical practice (cancer recurrence, fatal metastasis, and the refractory tumor microenvironment). Despite significant advances, improved molecular and cellular characterization of the tumor microenvironment is still required since it plays an important role in the genesis and progression of HCC. The purpose of this review is to present an overview of the HCC immune microenvironment, distinct cellular constituents, current therapies, and potential immunotherapy methods.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Recidiva Local de Neoplasia , Imunoterapia , Microambiente Tumoral , Sistema Imunitário/patologiaRESUMO
Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers. Early detection/diagnosis is vital for the prognosis of HCC, whereas diagnosis at late stages is associated with very low survival rate. Early diagnosis is based on 6-month surveillance of the patient and the use of at least two imaging modalities. The aim of this study was to investigate diagnostic markers for the detection of early HCC based on proteome analysis, microRNAs (miRNAs) and circulating tumor cells (CTCs) in the blood of patients with cirrhosis or early or advanced HCC. We studied 89 patients with HCC, of whom 33 had early HCC and 28 were cirrhotic. CTCs were detected by real-time quantitative reverse transcription PCR and immunofluorescence using the markers epithelial cell adhesion molecule (EPCAM), vimentin, alpha fetoprotein (aFP) and surface major vault protein (sMVP). Expression of the five most common HCC-involved miRNAs (miR-122, miR-200a, miR-200b, miR-221, miR-222) was examined in serum using quantitative real time PCR (qRT-PCR). Finally, patient serum was analyzed via whole proteome analysis (LC/MS). Of 53 patients with advanced HCC, 27 (51%) had detectable CTCs. Among these, 10/27 (37%) presented evidence of mesenchymal or intermediate stage cells (vimentin and/or sMVP positive). Moreover, 5/17 (29%) patients with early HCC and 2/28 (7%) cirrhotic patients had detectable CTCs. Patients with early or advanced HCC exhibited a significant increase in miR-200b when compared to cirrhotic patients. Our proteome analysis indicated that early HCC patients present a significant upregulation of APOA2, APOC3 proteins when compared to cirrhotic patients. When taken in combination, this covers the 100% of the patients with early HCC. miR-200b, APOA2 and APOC3 proteins are sensitive markers and can be potentially useful in combination for the early diagnosis of HCC.
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Ketamine, a phencyclidine derivative and N-methyl-D-aspartate (NMDA) receptor antagonist, is widely used as an anesthetic, analgesic, and sedative agent in daily pediatric practice. Experimental studies have suggested that early prenatal or postnatal exposure to ketamine can induce neuroapoptosis, and establish neurobehavioral deficits that are evident in adulthood. However, most of the currently available clinical evidence is derived from retrospective and observational clinical studies. We, herein, attempt a brief review of the cellular and molecular mechanisms suggested to mediate ketamine-induced developmental neurotoxicity, utilizing a selected number of recent in vivo experimental evidence.
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IGF-1 is one of the key molecules in cancer biology; however, little is known about the role of the preferential expression of the premature IGF-1 isoforms in prostate cancer. We have examined the role of the cleaved COO- terminal peptide (PEc) of the third IGF-1 isoform, IGF-1Ec, in prostate cancer. Our evidence suggests that endogenously produced PEc induces cellular proliferation in the human prostate cancer cells (PC-3) in vitro and in vivo, by activating the ERK1/2 pathway in an autocrine/paracrine manner. PEc overexpressing cells and tumors presented evidence of epithelial to mesenchymal transition, whereas the orthotopic injection of PEc-overexpressing, normal prostate epithelium cells (HPrEC) in SCID mice was associated with increased metastatic rate. In humans, the IGF-1Ec expression was detected in prostate cancer biopsies, where its expression correlates with tumor stage. Our data describes the action of PEc in prostate cancer biology and defines its potential role in tumor growth, progression and metastasis.
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Fator de Crescimento Insulin-Like I/metabolismo , Peptídeos/metabolismo , Neoplasias da Próstata/metabolismo , Animais , Comunicação Autócrina , Biópsia , Linhagem Celular Tumoral , Proliferação de Células , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal , Expressão Gênica , Xenoenxertos , Humanos , Fator de Crescimento Insulin-Like I/química , Fator de Crescimento Insulin-Like I/genética , Masculino , Camundongos , Camundongos SCID , Modelos Biológicos , Metástase Neoplásica , Comunicação Parácrina , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Isoformas de ProteínasRESUMO
Kisspeptin is an antimetastatic agent in some cancers that has also been associated with lymphoid cell apoptosis, a phenomenon favoring metastases. Our aim was to determine the association of kisspeptin with lymphocyte apoptosis and the presence of metastases in colorectal cancer patients. Blood was drawn from 69 colon cancer patients and 20 healthy volunteers. Tissue specimens from healthy and pathological tissue were immunohistochemically analyzed for kisspeptin and endothelial monocyte activating polypeptide II (EMAP-II) expression. Blood EMAP-II and soluble Fas ligand (sFasL) levels were examined by an enzyme-linked immunosorbent assay method. The kisspeptin and EMAP-II expression and secretion levels in the DLD-1 and HT-29 colon cancer cell lines were examined by quantitative real-time polymerase chain reaction, Western analysis and enzyme-linked immunosorbent assay, whereas lymphocyte viability was assessed by flow cytometry. The effect of kisspeptin on the viability of colon cancer cells was examined by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide]. Exogenous, synthetic and naturally produced, kisspeptin induces through the G-protein-coupled receptor 54 (GPR54; also known as the kisspeptin receptor) the EMAP-II expression and secretion in colon cancer cell lines, inducing in vitro lymphocyte apoptosis, as verified by the use of an anti-EMAP-II antibody. These results were reversed with the use of kisspeptin inhibitors and by kisspeptin-silencing experiments. Tumor kisspeptin expression was associated with the tumor EMAP-II expression (p < 0.001). Elevated kisspeptin and EMAP-II expression in colon cancer tissues was associated with lack of metastases (p < 0.001) in colon cancer patients. These data indicate the antimetastatic effect of tumor-elevated kisspeptin in colon cancer patients that may be mediated by the effect of kisspeptin on EMAP-II expression in colon cancer tumors in patients with normal serum EMAP-II levels. These findings provide new insight into the role of kisspeptin in the context of metastases in colon cancer patients.
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Apoptose/fisiologia , Neoplasias Colorretais/metabolismo , Citocinas/metabolismo , Kisspeptinas/metabolismo , Linfócitos/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas de Ligação a RNA/metabolismo , Idoso , Idoso de 80 Anos ou mais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Colorretais/patologia , Citocinas/sangue , Inativação Gênica , Humanos , Kisspeptinas/genética , Kisspeptinas/farmacologia , Linfócitos/efeitos dos fármacos , Pessoa de Meia-Idade , Proteínas de Neoplasias/sangue , Proteínas de Ligação a RNA/sangue , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Kisspeptina-1RESUMO
The Ki-67 antigen was identified in the early steps of polymerase I-dependent ribosomal RNA synthesis. Although it seems that this protein has an important function in cell division, its exact role is still unclear and there is little published work on its overall function. The aim of the present study was to evaluate the contribution of the level of Ki-67 with respect to tumor recurrence in molecularly classified groups of breast cancer patients. Ki-67 was divided into the percentage levels up to and including 20% and over 20%. Immunohistochemistry and fluorescence in-situ hybridization are described for the results of estrogen receptor, progesterone receptor, c-erb-B2, and Ki-67 biomarkers. Formaldehyde-fixed breast samples were paraffin wax embedded and processed for paraffin sections. The protocol of the present study started in 1995 and finished in 2010. Nine hundred and sixteen patients with breast cancer were examined: 291 were grouped as luminal A, 228 as luminal B, 221 as the Her-2 subtype, and 107 as basal cell (triple negative). Follow-up ranged from 3 to 15 years following diagnosis. It was found that in luminal A patients, only one had a Ki-67 level higher than 20%. In luminal B, the Ki-67 was higher than 20% in 51.16% of the patients and recurrence occurred in 23.68%. In the Her-2 subtype, the Ki-67 level was more than 20% in 48.63%. In basal cell triple-negative patients, Ki-67 was more than 20% in 63.86%. The data presented here indicate that the level of Ki-67 may be considered one of the valuable biomarkers in breast cancer patients with respect to process and recurrence.
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Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/diagnóstico , Proliferação de Células , Antígeno Ki-67/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Neoplasias da Mama/classificação , Neoplasias da Mama/patologia , Feminino , Humanos , Células MCF-7 , Camundongos Nus , Camundongos SCID , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/metabolismo , Prognóstico , Adulto JovemRESUMO
Cancer is among the leading causes of death worldwide. Early diagnosis and prognosis are vital to improve patients' outcomes. The gold standard of tumor characterization leading to tumor diagnosis and prognosis is tissue biopsy. Amongst the constraints of tissue biopsy collection is the sampling frequency and the incomplete representation of the entire tumor bulk. Liquid biopsy approaches, including the analysis of circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), circulating miRNAs, and tumor-derived extracellular vesicles (EVs), as well as certain protein signatures that are released in the circulation from primary tumors and their metastatic sites, present a promising and more potent candidate for patient diagnosis and follow up monitoring. The minimally invasive nature of liquid biopsies, allowing frequent collection, can be used in the monitoring of therapy response in real time, allowing the development of novel approaches in the therapeutic management of cancer patients. In this review we will describe recent advances in the field of liquid biopsy markers focusing on their advantages and disadvantages.
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INTRODUCTION: Osteosarcoma (OS) is the most common primary osseous malignant tumour, with high propensity to metastasise in lungs. Pulmonary micro-metastases are present in up to 80% of patients at initial diagnosis and they are associated with significantly worse prognosis. Doxycycline (Dox) is a synthetic tetracycline that has been shown to have anti-cancer properties in vitro and in vivo, and inhibit angiogenesis - effects that may prove beneficial for several types of cancer. The aim of the present work was to study how Dox affects OS cell growth in vitro and in vivo and OS-driven pulmonary metastasis in vivo. METHODS: In vitro, the effect of Dox was measured in MG-63 and 143B human OS cell viability, apoptosis, invasion and migration. In vivo, highly metastatic 143B cells were orthotopically implanted into the tibia of SCID mice. The tumour growth and pulmonary metastases between Dox treated and untreated, non-amputated and early amputated xenografts were examined. RESULTS: In vitro, Dox decreased viability, inhibited invasion, migration, and induced the apoptosis of OS cells. In vivo, Dox significantly enhanced tumour necrosis at primary OS sites, similarly to its in vitro effect, and downregulated the expression of Ki67, MMP2, MMP9, VEGFA and ezrin. It also decreased circulating VEGFA and MMP9 protein levels, in line with the decreased metastatic burden in Dox-treated mice (non-amputated and early-amputated). CONCLUSIONS: Reprofiling of Dox can prevent the evolvement of pulmonary micro-metastases to clinically detectable macro-metastases and suppress the lethal progress of OS by inhibiting the expression of MMPs, VEGFA and ezrin at primary sites.
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Neoplasias Ósseas , Neoplasias Pulmonares , Osteossarcoma , Animais , Neoplasias Ósseas/tratamento farmacológico , Linhagem Celular Tumoral , Proteínas do Citoesqueleto , Doxiciclina , Humanos , Neoplasias Pulmonares/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos SCID , Osteossarcoma/tratamento farmacológico , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Fator A de Crescimento do Endotélio VascularRESUMO
BACKGROUND: By alternative splicing the IGF-1 gene produces several different transcripts, including IGF-1Ec (MGF). The latter has been mainly associated with muscle regeneration processes. METHODS: We used immunohistochemistry, RT-PCR, and Western analysis to show the expression status of MGF in prostate tissue and human prostate cell lines (HPrEC, PC-3, and LNCaP) and we studied the exogenous administration of the MGF peptide E on cellular proliferation using trypan blue and MTT assays, before and after the silencing of the IGF-1 receptor and insulin receptor (siRNA methods). The MGF-induced intracellular activation was examined by Western analysis of the active forms of ERK1/2 and Akt. RESULTS: We documented that MGF is overexpressed in human prostate cancer (PCa) tissues and in human PC-3 and LNCaP cells. Notably, MGF expression was remarkably higher in PCa and prostatic intraepithelial neoplasia (PIN) than normal prostate tissues, while the normal prostate epithelial cells (HPrEC) did not express MGF. Exogenous administration of a synthetic MGF E peptide stimulated the PCa cell growth and activated ERK1/2 phosphorylation without affecting Akt phosphorylation. IGF-1R or insulin receptor (IR) silencing did not affect the mitogenic activity and intracellular signaling of the MGF E peptide in these PCa cells. CONCLUSIONS: These data suggest the possible implication of MGF E peptide in cancer biology, implying a preferential MGF expression in PCa tissues and cells. This preferential IGF-1 mRNA expression generates the MGF E peptide that possesses mitogenic activity through mechanisms independent of IGF-1R, IR, and hybrid IGF-1R/IR.
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Fator de Crescimento Insulin-Like I/biossíntese , Neoplasia Prostática Intraepitelial/metabolismo , Neoplasias da Próstata/metabolismo , Processamento Alternativo , Linhagem Celular Tumoral , Sobrevivência Celular/fisiologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Humanos , Fator de Crescimento Insulin-Like I/genética , Sistema de Sinalização das MAP Quinases , Masculino , Neoplasia Prostática Intraepitelial/enzimologia , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/genética , Isoformas de Proteínas , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/genética , Receptor IGF Tipo 1/biossíntese , Receptor IGF Tipo 1/genética , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
As the presence of tumor cells circulating in the blood is associated with systemic disease and shortened survival, the establishment of a method to detect circulating tumor cells (CTCs) is of critical importance for a more concise staging and follow-up of cancer patients. Recently, the most robust strategies for the determination of CTCs are the PCR-based methods and the CellSearch® system that exploits the immunofluorescent characterization and isolation of cancer cells. Herein, we analyzed the experimental strategies used for determining CTCs with respect to accuracy, sensitivity and reproducibility in cancers of the breast, colon, prostate and melanoma.
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Neoplasias/sangue , Células Neoplásicas Circulantes/patologia , Contagem de Células Sanguíneas , Células Sanguíneas/patologia , Separação Celular/métodos , Feminino , Humanos , Masculino , Metástase Neoplásica , Neoplasias/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodosRESUMO
BACKGROUND/AIM: Prostate cancer (PCa) is the second most commonly diagnosed cancer in men. In contrast to localized disease, metastatic PCa leads to increased mortality. Kisspeptin (KISS1) functions as a metastasis suppressor in various cancers. The aim of this study was to detect the expression of KISS1 and its receptor GPR54 (KISS1R) in prostate cancer. MATERIALS AND METHODS: The expression of KISS1 and KISS1R was examined in prostate cancer tissue specimens after radical prostatectomy. RESULTS: A higher expression of KISS1 and KISS1R was shown in patients with localized tumors (Stage ≤IIb) compared to patients with advanced (Stage ≥III) tumor. High Gleason score PCa and higher prognostic groups patients showed a lower expression rate of both KISS1 and KISS1R. CONCLUSION: A down-regulation of KISS1-KISS1R system was detected in advanced prostate cancer. KISS1as tumor suppressor might be useful in the future for the diagnosis, risk assessment of prostate cancer progression, as well as a therapeutic target for aggressive tumors.
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Kisspeptinas/biossíntese , Neoplasias da Próstata/metabolismo , Receptores de Kisspeptina-1/biossíntese , Idoso , Humanos , Imuno-Histoquímica , Kisspeptinas/metabolismo , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Receptores de Kisspeptina-1/genética , Receptores de Kisspeptina-1/metabolismoRESUMO
BACKGROUND: The glutamatergic system (Glu system) comprises the Glu receptors (GluRs), the Glu transporters (GluTs) and glutamine synthetase (GS). MATERIALS AND METHODS: Using PCR-based detection and Western blot analysis, the expression of Glu system components was assessed in human androgen-independent PC-3 and androgen-dependent LNCaP prostate cancer cells. RESULTS: iGluRs, such as NR1, NR2A, NR2C, NR2D and NR3B; mGLuRs such as mGluR1, mGluR2, mGluR3, mGluR4 and mGluR5; GluTs such as EAAT1, EAAT2, EAAT3 and EAATS; and GS mRNA were steadily expressed in both cell lines. In addition, NR3A, mGluR6, mGluR8 and EAAT4 mRNA were differentially expressed in PC-3 and LNCaP cells, mGluR7 and EAAT4 mRNA expression was induced and mGluR8 was silenced by dihydrotestosterone (DHT) treatment in LNCaP cells. GS, EAAT1 and mGLuR5 were also detected at the protein level in both PC-3 and LNCAP cells. CONCLUSION: These data suggest that the Glu system could be an important regulator of prostate cancer cell biology.
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Neoplasias Hormônio-Dependentes/metabolismo , Neoplasias da Próstata/metabolismo , Receptores de Glutamato/biossíntese , Linhagem Celular Tumoral , Humanos , Masculino , Neoplasias Hormônio-Dependentes/genética , Neoplasias da Próstata/genética , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Receptores de Glutamato/genéticaRESUMO
Kisspeptins are a family of neuropeptides that are known to be critical in puberty initiation and ovulation. Apart from that kisspeptin derived peptides (KPs) are also known for their antimetastatic activities in several malignancies. Herein we report recent evidence of the role of kisspeptins in cancer biology and we examine the prospective of targeting the kisspeptin pathways leading to a better prognosis in patients with malignant diseases.
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Kisspeptinas/metabolismo , Neoplasias/metabolismo , Transdução de Sinais , Animais , Feminino , Humanos , Masculino , Receptores de Kisspeptina-1/metabolismoRESUMO
Growth hormone (GH) regulated mainly liver-produced insulin-like growth factor 1 (IGF-1) is a key molecule in embryonic & post embryonic development that is also involved in cancer biology. Herein we review new insights of the role of igf-1 gene products and of the IGF-1Ec isoform in muscle and bone development/repair and its role in osteosarcoma pathophysiology, underlying the possible role of the Ec peptide as a future therapeutic target.
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Neoplasias Ósseas/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Osteossarcoma/metabolismo , Animais , Neoplasias Ósseas/genética , Neoplasias Ósseas/fisiopatologia , Humanos , Fator de Crescimento Insulin-Like I/genética , Osteossarcoma/genética , Osteossarcoma/fisiopatologia , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismoRESUMO
The Ec peptide (PEc) of insulin-like growth factor 1 Ec (IGF-1Ec) induces human mesenchymal stem cell (hMSC) mobilization and activates extracellular signalregulated kinase 1/2 (ERK 1/2) in various cells. The aim of the present study was to examine the effects of PEc on the mobilization and differentiation of hMSCs, as well as the possibility of its implementation in combination with transforming growth factor ß1 (TGFß1) for cartilage repair. The effects of the exogenous administration of PEc and TGFß1, alone and in combination, on hMSCs were assessed using a trypan blue assay, reverse transcription-quantitative polymerase chain reaction, western blot analysis, Alcian blue staining, wound healing assays and migration/invasion assays. It was determined that PEc is involved in the differentiation process of hMSCs towards hyaline cartilage. Treatment of hMSCs with either PEc, TGFß1 or both, demonstrated comparable cartilage matrix deposition. Furthermore, treatment with PEc in combination with TGFß1 was associated with a significant increase in hMSC mobilization when compared with treatment with TGFß1 or PEc alone (P<0.05). Thus, PEc appears to facilitate in vitro hMSC mobilization and differentiation towards chondrocytes, enhancing the role of TGFß1.
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Condrogênese/efeitos dos fármacos , Cartilagem Hialina/efeitos dos fármacos , Fator de Crescimento Insulin-Like I/farmacologia , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Peptídeos/farmacologia , Adulto , Proliferação de Células/efeitos dos fármacos , Separação Celular , Células Cultivadas , Colágeno/análise , Humanos , Cartilagem Hialina/citologia , Fator de Crescimento Transformador beta1/farmacologia , Cicatrização/efeitos dos fármacosRESUMO
OBJECTIVE: Preferential IGF-1Ec expression has been firmly associated with skeletal muscle repair mechanisms, post-infarction remodeling of the myocardium, the pathophysiology of endometriosis and prostate cancer biology. Therefore, we have studied the possible biological significance of synthetic Ec peptide, a putative cleavage product of IGF-1Ec in PC-3 cells and C2C12 myoblasts. DESIGN: We had previously designed and synthesized commercially peptides corresponding to the human Ec and its mouse igf1 counterpart as well as synthetic peptides that correspond to parts of the hEc. Using proliferation and mitogenic signaling assays, we tested their effect on PC-3 cells and C2C12 myoblasts at different doses and in different culture conditions. RESULTS: Human Ec, hEc, was documented as exerting progression but not competence growth factor actions, activating ERK1/2 without affecting Akt phosphorylation in PC-3 cells. A narrow concentration range of hEc (5-50nM) stimulated the growth of PC-3 cells grown in culture media supplemented with 10% FBS. hEc did not stimulate the growth of PC-3 cells cultured with media containing 0.5% FBS or in mouse C2C12 myoblasts under any culture conditions. The activity of hEc was blocked by a neutralizing anti-human IGF-1Ec antibody but not by a neutralizing anti-human IGF-1 receptor antibody. The synthetic mouse Ec was inactive in human PC-3 cells; however, it stimulated significantly the proliferation of mouse C2C12. By analyzing the bioactivity of synthetic hEc fragments, we documented that hEc's active core is located in the last 4aa of its C-terminal end. CONCLUSION: The hEc peptide is an important progression factor for human PC-3 prostate cancer cells.