In vitro evaluation of Axitinib and Sorafenib treatment in glioblastoma cell viability and morphology.

The formation, proliferation, and evolution of glioblastoma (GB) are significantly influenced by pathological angiogenesis. This is supported by several growth factor receptors, such as the vascular endothelial growth factor receptor (VEGFR). In this experiment, we examined how the Food and Drug Administration (FDA) approved VEGFR blockers Sorafenib and Axitinib affect the viability of GB cells in vitro. Cells were cultivated in 96-well culture plates for the experiments, afterwards Sorafenib and Axitinib were administered at doses ranging from 0.3 µM to 80 µM. 2,5-Diphenyl-2H-tetrazolium bromide (MTT) assay was used to assess the impact of VEGFR inhibition on high-grade glioma (HGG) cell lines. To observe the morphological changes in cell shape, we used a 10× magnification microscopy. Our results showed that both Axitinib and Sorafenib retarded GB1B culture proliferation in a dose- and time-dependent manner in comparison to control cohorts that had not received any treatment. The half maximal inhibitory concentration (IC50) value for Axitinib was 3.5839 µM after three days of drug administration and 2.2133 µM after seven days of drug administration. The IC50 value for Sorafenib was 3.5152 µM after three days of drug administration and 1.6846 µM after seven days of drug administration. After the treatment with Axitinib or Sorafenib, very few cells became rounded and detached from the support, others remained adherent to the culture substrate, but acquired a larger, flatter shape. Our results indicate that VEGFR might serve as a key target in the treatment of GB. Although it is known that in vitro some drugs block the VEGFR more potently, clinical evidence is required to show whether this actually translates to better clinical outcomes.

ELTD1 Review: New Regulator of Angiogenesis in Glioma.

Glioblastoma (GBM) is a severe brain cancer in which angiogenesis is controlled by G protein-coupled receptors (GPCRs), such as Epidermal Growth Factor Latrophilin and seven transmembrane domain-containing protein 1 (ELTD1), which are crucial for tumor progression. ELTD1 is an understudied GPCR with a broad expression profile in various tissues, including the human brain, especially in the cerebral cortex. It plays a significant role in angiogenesis and tumorigenesis and is regulated by interconnected VEGF and DLL4/Notch pathways. ELTD1 also modulates the JAK/STAT3/HIF-1α signaling axis, affecting the response of cells to low-oxygen conditions and promoting cell proliferation. However, their specific ligands and functional mechanisms remain unclear. ELTD1 expression is associated with different outcomes in various cancers. For example, in GBM, higher ELTD1 levels are linked to more mature and less leaky blood vessels, potentially enhancing drug delivery and therapeutic success. It also has divergent prognostic implications in renal, ovarian, and colorectal cancer. Additionally, ELTD1 overexpression in central nervous system endothelial cells suggests that it is a potential biomarker for multiple sclerosis. Therapeutically, blocking ELTD1 inhibits vessel formation, possibly slowing tumor growth. Initial therapies used polyclonal antibodies, but the shift has been towards more targeted monoclonal antibodies, particularly in preclinical glioma models. This review aimed to translate these insights into effective clinical treatments. However, several gaps remain in our knowledge regarding ELTD1 ligands and their potential involvement in other physiological or pathological processes that future research can address to elucidate the role of ELTD1 in cancer, through angiogenesis and other intracellular pathways.

Intracellular Pathways and Mechanisms of Colored Secondary Metabolites in Cancer Therapy.

Despite the great advancements made in cancer treatment, there are still many unsatisfied aspects, such as the wide palette of side effects and the drug resistance. There is an obvious increasing scientific attention towards nature and what it can offer the human race. Natural products can be used to treat many diseases, of which some plant products are currently used to treat cancer. Plants produce secondary metabolites for their signaling mechanisms and natural defense. A variety of plant-derived products have shown promising anticancer properties in vitro and in vivo. Rather than recreating the natural production environment, ongoing studies are currently setting various strategies to significantly manipulate the quantity of anticancer molecules in plants. This review focuses on the recently studied secondary metabolite agents that have shown promising anticancer activity, outlining their potential mechanisms of action and pathways.

Combined Effects of Doxorubicin and Temozolomide in Cultured Glioblastoma Cells.

The oncological field benefits of extensive medical research and various types of cancer notice improvements, however glioblastoma multiforme remains one of the deadliest cancers in humans with virtually no advance in survival and clinical outcome. Temozolomide, the FDA approved drug for glioblastoma, faces numerous challenges such as resistance and side effects. To overcome these challenges, many combination therapies are currently studied. The present study analyses the effects of temozolomide in combination with doxorubicin on a glioblastoma cell line. Our results showed that both drugs displayed a cytotoxic effect on the studied cells in single administration (55% for 100µM temozolomide at 14 days, 53% for 100µM doxorubicin at 14 days), but without a synergistic effect in dual therapy. Although the results failed to produce the expected effect, they propose new research perspectives in the future.

Impact of COVID-19 on fertility and assisted reproductive technology (ART): a systematic review.

The appearance of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been a major obstacle for the performing of current medical activities throughout the world. COVID-19 has affected humanity in many ways, thus causing a great medical, social, economic, and political instability. The aim of this study was to make an analysis of the scientific data obtained by so far to highlight the impact that COVID-19 has had on fertility and assisted reproductive technology (ART). Infection with SARS-CoV-2 alters the normal immune response by local and systemic damage to tissues and organs. After the virus enters the body, the first lesions are produced in the respiratory tract. Extrapulmonary lesions specific to COVID-19 include acute renal lesions/acute kidney damage, hepatocellular lesions, neurological diseases, myocardial dysfunction and arrhythmia, gastrointestinal diseases but also genital impairment. The possible impairment of the male reproductive system is because angiotensin-converting enzyme 2 (ACE2) receptors are in an increased number in the testes, seminiferous duct cells, spermatogonia, Leydig cells and Sertoli cells. Many published studies to date have pointed out that COVID-19 could also affect female fertility and disrupt the functions of the female reproductive system. The theory that this virus can also be transmitted sexually and can cause infertility or testicular damage is supported by the fact that the virus can be isolated in the semen of COVID-19 patients but only during the disease. Choosing the best method of treating infertility during the COVID-19 pandemic is multifactorial, but the risk of infection and compliance with specific ART hygiene protocols must always be considered. Currently, there is no scientific basis regarding the fact that the COVID-19 vaccination would influence fertility.

Updated Insights on EGFR Signaling Pathways in Glioma.

Nowadays, due to recent advances in molecular biology, the pathogenesis of glioblastoma is better understood. For the newly diagnosed, the current standard of care is represented by resection followed by radiotherapy and temozolomide administration, but because median overall survival remains poor, new diagnosis and treatment strategies are needed. Due to the quick progression, even with aggressive multimodal treatment, glioblastoma remains almost incurable. It is known that epidermal growth factor receptor (EGFR) amplification is a characteristic of the classical subtype of glioma. However, targeted therapies against this type of receptor have not yet shown a clear clinical benefit. Many factors contribute to resistance, such as ineffective blood-brain barrier penetration, heterogeneity, mutations, as well as compensatory signaling pathways. A better understanding of the EGFR signaling network, and its interrelations with other pathways, are essential to clarify the mechanisms of resistance and create better therapeutic agents.

The Potential of Helianthin Loaded Into Magnetic Nanoparticles to Induce Cytotoxicity in Glioblastoma Cells.

The central nervous system tumors are the most common solid tumors in adults.. Unlike other types of cancers, brain cancer is much difficult to treat because of the blood-brain barrier (BBB) that prevents drug substances from crossing it and accessing the brain. Different types of methods to overcome BBB have been used in vivo and in vitro, of which the use of nanoparticle-mediated delivery of therapeutic drugs is particularly promising. In the present study, we used iron oxide magnetic nanoparticles (NPs) as carrier system for helianthin (He/NPs) to treat cancer cells derived from glioblastoma. An early passage cell cultures (GB1B), established in our laboratory from tissue obtained from a patient diagnosed with glioblastoma, was used. The cells were treated with different concentrations of NPs or HeNPs and then cell proliferation was measured at 24, 48 and 72 hours. Our results showed that the treatment with NPs was well tolerated by glioblastoma cells, the viability of the cells increased very slightly after the treatment. Furthermore, we demonstrated that helianthin loaded Fe3O4 magnetic nanoparticles induced cytotoxicity in human glioblastoma cells. The treatment with HeNPs induced dose and time dependent.

The effect of temozolomide in combination with doxorubicin in glioblastoma cells in vitro.

BACKGROUND: Prior to 2000, the DNA alkylating agents nitrosoureas were used as standard treatment of glioblastoma. Current treatments for glioblastoma patients consist of surgery followed by radiation in combination with temozolomide. Despite therapeutic advances, the prognosis for glioblastoma patients remains grim, with a five-year overall survival below 15%. In this study, our team analyzed the interaction between temozolomide and doxorubicin in a glioblastoma cell line, in vitro. MATERIALS AND METHOD: The cell line, established from a patient who underwent surgery at the "Bagdasar Arseni Emergency Hospital", was exposed to 10 µM and 100 µM of temozolomide and 10 nM and 100 nM of doxorubicin, respectively, over a period of 7, 10 and 14 days, in monotherapy and in combination. RESULTS: The results showed that both temozolomide (66.5% cytotoxicity for the 10 µM dose at 14 days) de and doxorubicin (66.8% cytotoxicity for the 10 nM dose after 14 days) were very effective in killing cancer cells in monotherapy, but failed to produce a synergistic effect when used in combination. CONCLUSION: While the results may be discouraging, they present an interesting prospect into how certain drug interactions can impact treatment response.

Platelet-Derived Growth Factor Receptor and Ionizing Radiation in High Grade Glioma Cell Lines.

Treatment of high grade gliomas (HGGs) has remained elusive due to their high heterogeneity and aggressiveness. Surgery followed by radiotherapy represents the mainstay of treatment for HGG. However, the unfavorable location of the tumor that usually limits total resection and the resistance to radiation therapy are the major therapeutic problems. Chemotherapy with DNA alkylating agent temozolomide is also used to treat HGG, despite modest effects on survival. Disregulation of several growth factor receptors (GFRs) were detected in HGG and receptor amplification in glioblastoma has been suggested to be responsible for heterogeneity propagation through clonal evolution. Molecularly targeted agents inhibiting these membrane proteins have demonstrated significant cytotoxicity in several types of cancer cells when tested in preclinical models. Platelet-derived growth factor receptors (PDGFRs) and associated signaling were found to be implicated in gliomagenesis, moreover, HGG commonly display a Platelet-derived growth factor (PDGF) autocrine pathway that is not present in normal brain tissues. We have previously shown that both the susceptibility towards PDGFR and the impact of the PDGFR inactivation on the radiation response were different in different HGG cell lines. Therefore, we decided to extend our investigation, using two other HGG cell lines that express PDGFR at the cell surface. Here, we investigated the effect of PDGFR inhibition alone or in combination with gamma radiation in 11 and 15 HGG cell lines. Our results showed that while targeting the PDGFR represents a good means of treatment in HGG, the combination of receptor inhibition with gamma radiation did not result in any discernable difference compared to the single treatment. The PI3K/PTEN/Akt/mTOR and Ras/Raf/MEK/ERK pathways are the major signaling pathways emerging from the GFRs, including PDGFR. Decreased sensitivity to radiation-induced cell death are often associated with redundancy in these pro-survival signaling pathways. Here we found that Phosphoinositide 3-kinases (PI3K), Extracellular-signal-regulated kinase 1/2 (ERK1/2), or c-Jun N-terminal kinase 1/2 (JNK1/2) inactivation induced radiosensitivity in HGG cells.

Comparative effect of immunotherapy and standard therapy in patients with high grade glioma: a meta-analysis of published clinical trials.

Immunotherapy holds great promise in the treatment of high grade glioma (HGG). We performed a comprehensive meta-analysis of clinical trials involving dendritic cell (DC) therapy and viral therapy (VT) for the treatment of HGG, in order to assess their clinical impact in comparison to standard treatments in terms of overall survival (OS) and progression-free survival (PFS). To our knowledge, this is the first meta-analysis to evaluate VT for the treatment of HGG, allowing comparison of different immunotherapeutic approaches. Thirteen eligible studies of 1043 cases were included in the meta-analysis. For DC vaccination, in terms of OS, both newly diagnosed patients (HR, 0.65) and patients who suffered from recurrent HGGs (HR = 0.63) presented markedly improved results compared to the control groups. PFS was also improved (HR = 0.49) but was not statistically significant (p = 0.1). A slight improvement was observed for newly diagnosed patients receiving VT in terms of OS (HR = 0.88) while PFS was inferior for patients in the experimental arm (HR = 1.16). Our results show that DC therapy greatly improves OS for patients with both newly diagnosed and recurrent HGGs. VT, however, did not provide any statistically significant improvements in terms of OS and PFS for patients with newly diagnosed HGGs.

Current and emerging EGFR therapies for glioblastoma.

Glioblastomas (GBMs) are the most lethal and hard to treat malignancies in clinical practice. The standard of care for treating GBM involving surgery and adjuvant radiotherapy and concomitant temozolomide (TMZ) has remained virtually unchanged in the past decade. Molecular targeted therapies against cancer-specific structures have reported mediocre results in the treatment of GBM, due to multiple factors such as the presence of the blood brain barrier or a vast array of molecular alterations which greatly hinder the action of the most therapeutic agents. One such therapy is directed against the epidermal growth factor (EGF) and its' receptor (EGFR) using either monoclonal antibodies or tyrosine kinase inhibitors. Even though anti-EGF/EGFR treatment produced encouraging results in other forms of cancer it failed to present any clinical benefit for patients with GBM. Lately, immunotherapies that focus on using the host's own immune system against cancer cells have gained popularity, with approaches like peptide vaccination being successfully used in clinical trials for different types of malignancies. These immune-based therapies could hold the key to improving both the prognosis and quality of life for patients suffering for cancers previously considered incurable, such as GBM.

Two girl patients with medulloblastoma. Case reports.

In childhood, the most common type of brain tumors is medulloblastoma, a highly malignant primary brain tumor that is found in the cerebellum or posterior fossa. The tumor mass increases and generates obstructive hydrocephalus. Risk factors (that might be involved in some cases) include the genetic syndrome such as type 1 neurofibromatosis, exposure to ionizing radiation and Epstein-Barr virus. Medulloblastoma is associated with recessively inherited Turcot disease and with conditions as ataxia-telangiectasia syndrome in several cases. The authors presented two cases of female patients (aged one year and eight months old, respectively 4-year-old), both of them with weight deficiency, with personal history of head trauma. First case, M.D.M., was admitted in Emergency Room of the Emergency County Hospital, Craiova, Romania, for symptoms that included headaches, impaired vision, vomiting, mental disorders, ataxia and body imbalance. The reason for refer to the Surgical Unit care was posterior fossa tumor diagnosed by computed tomography (CT) scan. The second case, V.F., a 4-year-old girl, was admitted to First Pediatrics Clinic of the same Hospital, on October 2014, for seizures, early morning vomiting, loss of appetite, inability to walk and stand and also, mental delay. She had "café au lait" spots on her trunk, suggesting type 1 neurofibromatosis. A brain CT scan revealed a tumor being developed in the fourth ventricle (in the vermis of the cerebellum). Both the girls underwent curative surgery in different Clinics from Bucharest. The two girls with the same diagnosis showed contrasting post-surgical evolution: M.D.M. still survives, while V.F. survived only for six months following first surgical intervention. The first patient, M.D.M., received chemotherapy before and after the surgery, which a slow but favorable recovery noted. For the second patient, the brain CT scan performed four months after surgery showed multiple masses in the cerebral posterior fossa, suggestive of leptomeningeal metastases, but without local recurrence of the medulloblastoma. The patient started chemotherapy and, after two sessions, she went for second surgical treatment. Six months after the second surgery, the second female patient, V.F., died. The objective of this study is to find the reasons of their different clinical evolution. The authors emphasized the clinical similarities of the patients, both being female, having similar symptoms and incidental medical events (upper and lower respiratory tract infections and head trauma) but most important, they stressed out the factors which contributed to the different clinical outcome, the second patient having a more aggressive form of medulloblastoma and receiving chemotherapy only after leptomeningeal metastases were evidenced. In addition, as for the second patient, she might had clinical criteria for type 1 neurofibromatosis (the author specified the number of the "café au lait" spots being over 6, like her brother, mental delay, without other clinical signs), which might have contributed to the poor outcome. The etiology of medulloblastoma can also be involved with chromosome 17 and the diagnosis of such a brain tumor can be an evolutive criterion for neurofibromatosis. The diagnosis can provided only by genetic tests. There is a vital risk and a reason for the lethal evolution of V.F. PATIENT: As medulloblastoma is a very aggressive malignant tumor, the approximate cumulative survival rate for preschool age group having a histological follow-up was found to be 47% over a span of five years of rigorous treatment.

Silencing of epidermal growth factor, latrophilin and seven transmembrane domain-containing protein 1 (ELTD1) via siRNA-induced cell death in glioblastoma.

The failure of therapies targeting tumor angiogenesis may be caused by anti-angiogenic resistance mechanisms induced by VEGF and non-VEGF pathways alterations. Anti-angiogenic therapy failure is also attributed to immune system, acting by tumor-associated macrophages that release pro-angiogenic factors and a consequent increase of blood vessels. Recently, in a study by Rheal et al., a new angiogenic receptor, epidermal growth factor, latrophilin, and 7 trans-membrane domain-containing protein 1 on chromosome 1(ELTD1) has been identified as a promising glioma biomarker. In this study we aim to analyse whether this receptor may be used as a target molecule in glioblastoma therapy. Our results showed that small interfering RNA silencing ELTD1 caused cytotoxicity in glioblastoma cells. We also found that PDGFR, VEGFR, and their common PI3K/mTOR intracellular pathway inactivation-induced cytotoxicity in glioblastoma cells. Further, we found high percent of cytotoxicity in a low passage glioblastoma cell line after BEZ235 (a dual inhibitor of PI3K/mTOR pathway) treatment at nanomolar concentrations, compared to AG1433 (a PDGFR inhibitor) and SU1498 (a VEGFR inhibitor) that were only cytotoxic at micromolar ranges. In the future, these could prove as attractive therapeutic targets in single therapy or coupled with classic therapeutic approaches such as chemotherapy of radiotherapy.

Targeting the VEGF and PDGF signaling pathway in glioblastoma treatment.

Growth factor receptors dysfunction has previously been correlated with glioma cell proliferation, ability to evade apoptosis, neo-angiogenesis and resistance to therapy. Antineoplastic molecules targeting growth factor receptors are in clinical handling, however the efficacy of these compounds has often been limited by the signaling redundancy. Here, we analyzed the effect of AG1433 (a PDGFR inhibitor), SU1498 (a VEGFR inhibitor) and BEZ235 (a PI3K/Akt/mTOR signaling pathways inhibitor) on glioblastoma cells in vitro. For this study, we used a low passage glioblastoma cell line (GB9B). Assessment of cell number over 72 h showed that the growth rate was 0.3024 and the doubling time of GB9B was 2.29 days. Similar cytotoxic effects were observed by using AG1433 and SU1498 treatment, while dual PI3K/Akt/mTOR inhibition by BEZ235 was more efficient in killing glioblastoma cells than individual PDGFR or VEGFR targeting. In SU1498 treated cells, caspase 3 activity was detected 3 hours after the treatment, while activation of caspase 8 and 9 was detected 48 hours later. AG1433 treatment induced caspase 3, 8 and 9, 3 hours after the treatment. BEZ235 treatment resulted in early caspase 3 and 8 activation, 3 hours after the treatment and an activation of caspase 9, 8 hours later.

Epidermal growth factor, latrophilin, and seven transmembrane domain-containing protein 1 marker, a novel angiogenesis marker.

Epidermal growth factor, latrophilin, and seven transmembrane domain-containing protein 1 on chromosome 1 (ELTD1), an orphan adhesion G-protein coupled receptor, was reported as a regulator of angiogenesis, also involved in cancer progression and development. More recently, ELTD1 was identified as a potential new tumor marker for high-grade glioma. ELTD1, belongs to the G-protein coupled receptor superfamily that comprises the biggest receptor family in the human genome. Following the discovery of ELTD1 almost a decade ago, only a few research groups have attempted to find its role in normal and tumor cells, important information about this receptor remaining still unknown. The ELTD1 ligand has not currently been identified and intracellular signaling studies have not yet been performed in normal or tumor cells. Although the current published data on ELTD1 function and structure are rather limited, this receptor seems to be very important, not only as biomarker, but also as molecular target in glioblastoma. This review summarizes and discusses the current knowledge on ELTD1 structure, function, and its role in both physiological and tumoral angiogenesis.

Inducible nitric oxide synthase expression (iNOS) in chronic viral hepatitis and its correlation with liver fibrosis.

BACKGROUND: Nitric oxide (NO) production by the action of the inducible nitric oxide synthase (iNOS or NOS2) is increased in tissues that are stimulated by cytokine and endotoxins. The role of NO in the pathogenesis of chronic viral hepatitis is not fully understood but it seems that its overproduction is responsible for the pathological changes under inflammatory conditions. AIM: In this paper, we analyzed the correlation between immunohistochemical expression of iNOS and liver fibrosis in chronic viral hepatitis. MATERIALS AND METHODS: Liver biopsies from patients diagnosed with chronic viral hepatitis B and C were embedded in paraffin and further used for histological staining and immunohistochemical reactions to detect the expression of iNOS and TGF-ß1. The degree of liver fibrosis was established using special staining (trichromic Masson and Gömöri's silver impregnation). RESULTS: In samples with low degree of fibrosis, we observed a discrete positivity for iNOS in periportal hepatocytes and the immunohistochemical reaction for TGF-ß1 were limited to the endothelial cells of liver sinusoids and pro-inflammatory cells from the portal tracts. Positive reaction for TGF-ß1 increased with the degree of liver fibrosis, while the expression of iNOS was enhanced in hepatocytes, as well as in bile ducts and endothelial cells. CONCLUSIONS: Infection with hepatitis B and C viruses induces iNOS expression in hepatocytes, suggesting that NO overproduction might have an important role in progression of chronic viral hepatitis to cirrhosis.

Cancer stem cells: biological functions and therapeutically targeting.

Almost all tumors are composed of a heterogeneous cell population, making them difficult to treat. A small cancer stem cell population with a low proliferation rate and a high tumorigenic potential is thought to be responsible for cancer development, metastasis and resistance to therapy. Stem cells were reported to be involved in both normal development and carcinogenesis, some molecular mechanisms being common in both processes. No less controversial, stem cells are considered to be important in treatment of malignant diseases both as targets and drug carriers. The efforts to understand the role of different signalling in cancer stem cells requires in depth knowledge about the mechanisms that control their self-renewal, differentiation and malignant potential. The aim of this paper is to discuss insights into cancer stem cells historical background and to provide a brief review of the new therapeutic strategies for targeting cancer stem cells.

Plasma levels of glucose and insulin in patients with brain tumors.

In the last years there were many authors that suggest the existence of an association between different components of metabolic syndrome and various cancers. Two important components of metabolic syndrome are hyperglycemia and hyperinsulinemia. Both of them had already been linked with the increased risk of pancreatic, breast, endometrial or prostate cancer. However the correlation of the level of the glucose and insulin with various types and grades of brain tumors remains unclear. In this article we have analysed the values of plasma glucose and insulin in 267 patients, consecutively diagnosed with various types of brain tumors. Our results showed no correlation between the glycemia and brain tumor types or grades. High plasma levels of insulin were found in brain metastasis and astrocytomas while the other types of brain tumors (meningiomas and glioblastomas) had lower levels of the peptide. The levels of insulin were also higher in brain metastasis and grade 3 brain tumors when compared with grade 1, grade 2 and grade 4 brain tumors.

Biobanking in a constantly developing medical world.

Biobank is a very sophisticated system that consists of a programmed storage of biological material and corresponding data. Biobanks are created to be used in medical research, in clinical and translational medicine, and in healthcare. In the past 20 years, a large number of biobanks have been set up around the world, to support the modern research directions in medicine such as omix and personalized medicine. More recently, embryonic and adult stem cell banks have been developed. Stem cell banking was reported to be required for medical research as well as clinical transplant applications. The quality of the samples stored in a biobank is very important. The standardization is also important; the biological material stored in a biobank must be processed in a manner that allows compatibility with other biobanks that preserve samples in the same field. In this paper, we review some issues related to biobanks purposes, quality, harmonization, and their financial and ethical aspects.

Tropomyosin-receptor-kinases signaling in the nervous system.

ABSTRACT: The development and function of the nervous system is dependent on many growth factors and their signaling. Tropomyosin-receptor-kinase receptor family controls synaptic strength and plasticity in the mammalian nervous system. Dysregulation of Tropomyosin-receptor-kinase receptors signaling can lead to neural developmental disorders and has been reported in certain diseases of the nervous system. Apart from their role in the nervous system, these tyrosine kinase receptors are also involved in cancer biology. Tropomyosin-receptor-kinases and their ligands, neurotrophins, are also involved in neural precursor stem cells differentiation. This review focuses on Tropomyosin-receptor-kinases, the most abundant receptors in mammalian nervous system.