Utilizing Exosomal-EPHs/Ephrins as Biomarkers and as a Potential Platform for Targeted Delivery of Therapeutic Exosomes

Exosomes are cell-secreted nanoparticles containing various molecules including small vesicles, microRNAs (miRNAs), messenger RNAs or bioactive proteins which are thought to be of paramount importance for intercellular communication. The unique effects of exosomes in terms of cell penetration capacity, decreased immunogenicity and inherent stability, along with their key role in mediating information exchange among tumor cells and their surrounding tumor microenvironment (TME), render them a promising platform for drug targeted delivery. Compared to synthetic drugs, exosomes boast a plethora of advantages, including higher biocompatibility, lower toxicity and increased ability of tissue infiltration. Nevertheless, the use of artificial exosomes can be limited in practice, partly due to their poor targeting ability and partly due to their limited efficacy. Therefore, efforts have been made to engineer stem cell-derived exosomes in order to increase selectiveness and effectivity, which can then become loaded with various active substances depending on the therapeutic approach followed. Erythropoietin-producing human hepatocellular receptors (EPHs), along with their ligands, the EPH family receptor interacting proteins (ephrins), have been extensively investigated for their key roles in both physiology and cancer pathogenesis. EPHs/ephrins exhibit both tumorigenic and tumor suppressing properties, with their targeting representing a promising, novel therapeutic approach in cancer patients’ management. In our review, the use of ephrin-loaded exosomes as a potential therapeutic targeted delivery system in cancer will be discussed

The EPH/Ephrin System in Colorectal Cancer

The EPH/ephrin system constitutes a bidirectional signaling pathway comprised of a family of tyrosine kinase receptors in tandem with their plasma membrane-bound ligand (ephrins). Its significance in a wide variety of physiologic and pathologic processes has been recognized during the past decades. In carcinogenesis, EPH/ephrins coordinate a wide spectrum of pathologic processes, such as angiogenesis, vessel infiltration, and metastasis. Despite the recent advances in colorectal cancer (CRC) diagnosis and treatment, it remains a leading cause of death globally, accounting for 9.2% of all cancer deaths. A growing body of literature has been published lately revitalizing our scientific interest towards the role of EPH/ephrins in pathogenesis and the treatment of CRC. The aim of the present review is to present the recent CRC data which might lead to clinical practice changes in the future

Thymic Epithelial Neoplasms: Focusing on the Epigenetic Alterations

Thymic Epithelial Neoplasms (TENs) represent the most common tumors of the thymus gland. Epigenetic alterations are generally involved in initiation and progression of various cancer entities. However, little is known about the role of epigenetic modifications in TENs. In order to identify relevant studies, a literature review was conducted using the MEDLINE and LIVIVO databases. The search terms thymoma, thymic carcinoma, thymic epithelial neoplasm, epigenetics, DNA methylation, HDAC and miRNA were employed and we were able to identify forty studies focused on TENs and published between 1997 and 2021. Aberrant epigenetic alterations seem to be involved in the tumorigenesis of thymomas and thymic carcinomas, with numerous studies reporting on non-coding RNA clusters and altered gene methylation as possible biomarkers in different types of TENs. Interestingly, Histone Deacetylase Inhibitors have shown potent antitumor effects in clinical trials, thus possibly representing effective epigenetic therapeutic agents in TENs. Additional studies in larger patient cohorts are, nevertheless, needed to verify the clinical utility and safety of novel epigenetic agents in the treatment of patients with TENs

The EPH/Ephrin System in Gynecological Cancers: Focusing on the Roots of Carcinogenesis for Better Patient Management

Gynecological cancers represent some of the most common types of malignancy worldwide. Erythropoietin-producing hepatocellular receptors (EPHs) comprise the largest subfamily of receptor tyrosine kinases, binding membrane-bound proteins called ephrins. EPHs/ephrins exhibit widespread expression in different cell types, playing an important role in carcinogenesis. The aim of the current review was to examine the dysregulation of the EPH/ephrin system in gynecological cancer, clarifying its role in ovarian, endometrial, and cervical carcinogenesis. In order to identify relevant studies, a literature review was conducted using the MEDLINE and LIVIVO databases. The search terms ephrin, ephrin receptor, ovarian cancer, endometrial cancer, and cervical cancer were employed and we were able to identify 57 studies focused on gynecological cancer and published between 2001 and 2021. All researched ephrins seemed to be upregulated in gynecological cancer, whereas EPHs showed either significant overexpression or extensive loss of expression in gynecological tumors, depending on the particular receptor. EPHA2, the most extensively studied EPH in ovarian cancer, exhibited overexpression both in ovarian carcinoma cell lines and patient tissue samples, while EPHB4 was found to be upregulated in endometrial cancer in a series of studies. EPHs/ephrins were shown to exert their role in different stages of gynecological cancer and to influence various clinicopathological parameters. The analysis of patients’ gynecological cancer tissue samples, most importantly, revealed the significant role of the EPH/ephrin system in the development and progression of gynecological cancer, as well as overall patient survival. In conclusion, the EPH/ephrin system represents a large family of biomolecules with promising applications in the fields of diagnosis, prognosis, disease monitoring, and treatment of gynecological cancer, with an established important clinical impact

The Role of PROX1 in Neoplasia: A Key Player Often Overlooked

The human PROX1 gene (Prospero homeobox gene 1) is a member of the homeobox transcription factor family. PROX1 plays a key role in the development of the lymphatic system and is primarily used as a lymphatic vessel marker. However, as the accumulating evidence indicates that PROX1 is also implicated in the tumorigenesis of various cancer types, the scientific community has attempted to elucidate its complicated function in neoplasia pathogenesis, as well as its utility in cancer diagnosis, prognosis, and therapy. PROX1 has been shown to participate in the complex molecular mechanisms affecting tumorigenesis and has been associated with a plethora of clinicopathological parameters, including tumor stage and patients’ overall survival. Depending on the specific organ affected, PROX1 has exhibited both tumor-promoting and tumor-suppressing properties, with its inhibition and reactivation representing possible novel therapeutic interventions, respectively. Moreover, researchers have reported PROX1 as a useful tool in the fields of diagnosis and prognosis assessment. The current study aims to summarize and present the existing data that render PROX1 a novel and useful diagnostic and prognostic biomarker, as well as a possible therapeutic target

Thymic Epithelial Neoplasms: Focusing on the Epigenetic Alterations

Thymic Epithelial Neoplasms (TENs) represent the most common tumors of the thymus gland. Epigenetic alterations are generally involved in initiation and progression of various cancer entities. However, little is known about the role of epigenetic modifications in TENs. In order to identify relevant studies, a literature review was conducted using the MEDLINE and LIVIVO databases. The search terms thymoma, thymic carcinoma, thymic epithelial neoplasm, epigenetics, DNA methylation, HDAC and miRNA were employed and we were able to identify forty studies focused on TENs and published between 1997 and 2021. Aberrant epigenetic alterations seem to be involved in the tumorigenesis of thymomas and thymic carcinomas, with numerous studies reporting on non-coding RNA clusters and altered gene methylation as possible biomarkers in different types of TENs. Interestingly, Histone Deacetylase Inhibitors have shown potent antitumor effects in clinical trials, thus possibly representing effective epigenetic therapeutic agents in TENs. Additional studies in larger patient cohorts are, nevertheless, needed to verify the clinical utility and safety of novel epigenetic agents in the treatment of patients with TENs

Exosomes in the Treatment of Pancreatic Cancer: A Moonshot to PDAC Treatment?

Pancreatic Ductal Adenocarcinoma (PDAC) constitutes a leading cause of cancer death globally. Its mortality remains unaltered despite the considerable scientific progress made in the fields of diagnostics and treatment. Exosomes comprise of small extracellular vesicles secreted by nearly all cells; their cargo contains a vast array of biomolecules, such as proteins and microRNAs. It is currently established that their role as messengers is central to a plethora of both physiologic and pathologic processes. Accumulating data have shed light on their contributions to carcinogenesis, metastasis, and immunological response. Meanwhile, the advancement of personalized targeted therapies into everyday clinical practice necessitates the development of cost-efficient treatment approaches. The role of exosomes is currently being extensively investigated towards this direction. This review aims to summarize the current pre-clinical and clinical evidence regarding the effects of exosomal applications in the timely diagnosis, prognosis, and therapeutic management of pancreatic cancer

Exosomes in the Treatment of Pancreatic Cancer: A Moonshot to PDAC Treatment?

Pancreatic Ductal Adenocarcinoma (PDAC) constitutes a leading cause of cancer death globally. Its mortality remains unaltered despite the considerable scientific progress made in the fields of diagnostics and treatment. Exosomes comprise of small extracellular vesicles secreted by nearly all cells; their cargo contains a vast array of biomolecules, such as proteins and microRNAs. It is currently established that their role as messengers is central to a plethora of both physiologic and pathologic processes. Accumulating data have shed light on their contributions to carcinogenesis, metastasis, and immunological response. Meanwhile, the advancement of personalized targeted therapies into everyday clinical practice necessitates the development of cost-efficient treatment approaches. The role of exosomes is currently being extensively investigated towards this direction. This review aims to summarize the current pre-clinical and clinical evidence regarding the effects of exosomal applications in the timely diagnosis, prognosis, and therapeutic management of pancreatic cancer

Application of the International System for Reporting Serous Fluid Cytopathology with Cytohistological Correlation and Risk of Malignancy Assessment

The International System for Reporting Serous Fluid Cytopathology (TIS) classifies serous effusions into five categories: non-diagnostic (ND), negative for malignancy (NFM), atypia of unknown significance (AUS), suspicious for malignancy (SFM) and malignant (MAL). The main objectives of this classification comprise the establishment of a universal code of communication between cytopathologists and clinicians and histopathologists, as well as between different laboratories worldwide, paving the way for the setting of clinical management guidelines based on the risk of malignancy assessment for each diagnostic category. We retrieved the total number of pleural and peritoneal effusion cases of our department for the three-year time period between 2018 and 2020, yielding a total of 528 and 500 cases, respectively. We then proceeded to reclassify each specimen according to TIS guidelines and calculate the risk of malignancy (ROM) for each category by searching each patients’ histology records, medical history and clinical follow-up. For pleural effusions, 3 (0.57%) cases were classified as ND, 430 (81.44%) cases as NFM, 15 (2.84%) as AUS, 15 (2.84%) as SFM and 65 (12.31%) as MAL. ROM amounted to 0%, 5.3%, 33.33%, 93.33% and 100% for each category, respectively. As far as peritoneal effusions are concerned, 6 (1.2%) were categorized as ND with ROM estimated at 16.66%, 347 (69.4%) as NFM (ROM = 9%), 13 (2.6%) as AUS (ROM = 38.46%), 12 (2.4%) as SFM (ROM = 83.33%) and 122 (24.4%) as MAL (ROM = 100%). Our results underline the utility of the current classification, both as a means of communication between doctors of different specialties and as general guidelines for the further clinical management of patients

Application of the International System for Reporting Serous Fluid Cytopathology with Cytohistological Correlation and Risk of Malignancy Assessment

The International System for Reporting Serous Fluid Cytopathology (TIS) classifies serous effusions into five categories: non-diagnostic (ND), negative for malignancy (NFM), atypia of unknown significance (AUS), suspicious for malignancy (SFM) and malignant (MAL). The main objectives of this classification comprise the establishment of a universal code of communication between cytopathologists and clinicians and histopathologists, as well as between different laboratories worldwide, paving the way for the setting of clinical management guidelines based on the risk of malignancy assessment for each diagnostic category. We retrieved the total number of pleural and peritoneal effusion cases of our department for the three-year time period between 2018 and 2020, yielding a total of 528 and 500 cases, respectively. We then proceeded to reclassify each specimen according to TIS guidelines and calculate the risk of malignancy (ROM) for each category by searching each patients’ histology records, medical history and clinical follow-up. For pleural effusions, 3 (0.57%) cases were classified as ND, 430 (81.44%) cases as NFM, 15 (2.84%) as AUS, 15 (2.84%) as SFM and 65 (12.31%) as MAL. ROM amounted to 0%, 5.3%, 33.33%, 93.33% and 100% for each category, respectively. As far as peritoneal effusions are concerned, 6 (1.2%) were categorized as ND with ROM estimated at 16.66%, 347 (69.4%) as NFM (ROM = 9%), 13 (2.6%) as AUS (ROM = 38.46%), 12 (2.4%) as SFM (ROM = 83.33%) and 122 (24.4%) as MAL (ROM = 100%). Our results underline the utility of the current classification, both as a means of communication between doctors of different specialties and as general guidelines for the further clinical management of patients