Pro-tumorigenic role of type 2 diabetes-induced cellular senescence in colorectal cancer

Colorectal cancer (CRC) is the second leading cause of cancer-related mortality worldwide. The disease still remains incurable and highly lethal in the advanced stage, representing a global health concern. Therefore, it is essential to understand the causes and risk factors leading to its development. Because age-related cellular senescence and type 2 diabetes (T2D) have been recognised as risk factors for CRC development, the recent finding that type 2 diabetic patients present an elevated circulating volume of senescent cells raises the question whether type 2 diabetes facilitates the process of CRC tumorigenesis by inducing premature cell senescence. In this review, we will discuss the mechanisms according to which T2D induces cellular senescence and the role of type 2 diabetes-induced cellular senescence in the pathogenesis and progression of colorectal cancer. Lastly, we will explore the current therapeutic approaches and challenges in targeting senescence

The mechanistic immunosuppressive role of the tumour vasculature and potential nanoparticle-mediated therapeutic strategies

The tumour vasculature is well-established to display irregular structure and hierarchy that is conducive to promoting tumour growth and metastasis while maintaining immunosuppression. As tumours grow, their metabolic rate increases while their distance from blood vessels furthers, generating a hypoxic and acidic tumour microenvironment. Consequently, cancer cells upregulate the expression of pro-angiogenic factors which propagate aberrant blood vessel formation. This generates atypical vascular features that reduce chemotherapy, radiotherapy, and immunotherapy efficacy. Therefore, the development of therapies aiming to restore the vasculature to a functional state remains a necessary research target. Many anti-angiogenic therapies aim to target this such as bevacizumab or sunitinib but have shown variable efficacy in solid tumours due to intrinsic or acquired resistance. Therefore, novel therapeutic strategies such as combination therapies and nanotechnology-mediated therapies may provide alternatives to overcoming the barriers generated by the tumour vasculature. This review summarises the mechanisms that induce abnormal tumour angiogenesis and how the vasculature’s features elicit immunosuppression. Furthermore, the review explores examples of treatment regiments that target the tumour vasculature

Advances in anti-cancer immunotherapy: car-T cell, checkpoint inhibitors, dendritic cell vaccines, and oncolytic viruses, and emerging cellular and molecular targets

Unlike traditional cancer therapies, such as surgery, radiation and chemotherapy that are typically non-specific, cancer immunotherapy harnesses the high specificity of a patient’s own immune system to selectively kill cancer cells. The immune system is the body’s main cancer surveillance system, but cancers may evade destruction thanks to various immune-suppressing mechanisms. We therefore need to deploy various immunotherapy-based strategies to help bolster the anti-tumour immune responses. These include engineering T cells to express chimeric antigen receptors (CARs) to specifically recognise tumour neoantigens, inactivating immune checkpoints, oncolytic viruses and dendritic cell (DC) vaccines, which have all shown clinical benefit in certain cancers. However, treatment efficacy remains poor due to drug-induced adverse events and immunosuppressive tendencies of the tumour microenvironment. Recent preclinical studies have unveiled novel therapies such as anti-cathepsin antibodies, galectin-1 blockade and anti-OX40 agonistic antibodies, which may be utilised as adjuvant therapies to modulate the tumour microenvironment and permit more ferocious anti-tumour immune response

Blastic Plasmacytoid Dendritic Cell Neoplasm

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Gamma-ray irradiation modulates PGRMC1 expression and the number of CD56⁺ and FoxP3⁺ cells in the tumor microenvironment of endometrial endometrioid adenocarcinoma

Purpose Although the conventional gamma ray brachytherapy has been successful in treating endometrioid endometrial adenocarcinoma (EC), the molecular and cellular mechanisms of this anti-tumorigenic response remain unclear. Therefore, we investigated whether gamma ray irradiation induces changes in the number of FoxP3+ T-regulatory lymphocytes (Tregs), CD56+ natural killer cells (NK), and the expression of progesterone receptor membrane component 1 (PGRMC1) in the tumor microenvironment (TME). Materials and Methods According to the inclusion criteria, 127 cases were selected and grouped into irradiation-treated (Rad+) and control (underwent surgery) groups and analyzed using immunohistochemistry. Predictive prognostic values were analyzed using Mann-Whitney U test, ROC analysis, relative risk, log-rank, Spearman rank tests and multivariate Cox’s regression. Results We observed significant differences (p < 0.001) between the radiation-treated patients and the control groups in FoxP3+ Tregs numbers, CD56+ NK cells and PGRMC1 expression. Gamma ray induced a 3.71- and 3.39-fold increase in the infiltration of FoxP3+ cells, CD56+ NK cells, respectively and 0.0034-fold change in PGRMC1 expression. Univariate and multivariate analyses revealed predictive role of the parameters. In the irradiated patients’ group, inverted correlations between clinical unfavorable outcome, FoxP3+ Tregs and CD56+ NK cells were observed. Conclusion Our results suggest an immune-modulating role, specifically by increasing immune cell infiltration, of gamma radiation in the TME which may potentially be utilized as biomarkers in prognostic values

Potential role of diabetes mellitus‐associated T cell senescence in epithelial ovarian cancer omental metastasis

Epithelial ovarian cancer (EOC) is one of the most common causes of cancer‐related deaths among women and is associated with age and age‐related diseases. With increasing evidence of risks associated with metabolic inflammatory conditions, such as obesity and type 2 diabetes mellitus (T2DM), it is important to understand the complex pathophysiological mechanisms underlying cancer progression and metastasis. Age‐related conditions can lead to both genotypic and phenotypic immune function alterations, such as induction of senescence, which can contribute to disease progression. Immune senescence is a common phenomenon in the ageing population, which is now known to play a role in multiple diseases, often detrimentally. EOC progression and metastasis, with the highest rates in the 75–79 age group in women, have been shown to be influenced by immune cells within the “milky spots” or immune clusters of the omentum. As T2DM has been re-ported to cause T cell senescence in both prediabetic and diabetic patients, there is a possibility that poor prognosis in EOC patients with T2DM is partly due to the accumulation of senescent T cells in the omentum. In this review, we explore this hypothesis with recent findings, potential therapeutic approaches, and future directions

Prognostic value of immunohistochemical markers for locally advanced rectal cancer

The aim of this study is to reveal the potential roles of apoptosis markers (Bcl2 and p53), proliferation markers (Ki-67 and CyclD1), and the neuroendocrine marker Chromogranin A as markers for the radioresistance of rectal cancer. Statistically significant differences were found in the expression of p53, Ki-67, and Chromogranin A in groups of patients with and without a favorable prognosis after radiotherapy. The survival analysis revealed that the marker of neuroendocrine differentiation, Chromogranin A, also demonstrated a high prognostic significance, indicating a poor prognosis. Markers of proliferation and apoptosis had no prognostic value for patients who received preoperative radiotherapy. Higher Chromogranin A values were predictors of poor prognosis. The results obtained from studying the Chromogranin A expression suggest that the secretion of biologically active substances by neuroendocrine cells causes an increase in tumor aggressiveness

Endothelin-1 and Its Role in Cancer and Potential Therapeutic Opportunities

Endothelin-1 (ET-1) plays a physiological role as a potent vasoconstrictor. It is implicated in an array of diseases, and its signalling is often found to be overactivated within cancers. ET-1 has been found to potentiate hallmarks of cancer progression such as cell proliferation, invasion and metastasis, as well as angiogenesis. ET-1 has also been implicated in inducing the epithelial–mesenchymal transition (EMT) and promoting resistance to anticancer drugs. Many preclinical efforts have been made to target ET-1 expression within cancer, such as by using ET-1 receptor antagonists, many of which have been approved for treating pulmonary hypertension. Targeting ET-1 has been shown to improve the response to various other cancer therapeutics, highlighting the potential benefits targeting this peptide may exert. Drug repurposing is an attractive strategy, and exploration of this avenue may be promising for targeting ET-1 in cancer. There are many clinical trials which have been completed and are currently undergoing involving the repurposing of ET-1 receptor antagonists for cancer treatment. In this review, the pathways through which ET-1 potentiates cancer will be discussed, as well as where the opportunity for therapeutic intervention lies in relation to cancer

Increase in FoxP3, CD56 immune cells and decrease in glands PGRMC1 expression in the endometrium are associated with recurrent miscarriages

OBJECTIVE: Recurrent miscarriage (RM) is a multifactorial condition that involves frequent uterine anatomical abnormalities, parental karyotype abnormalities, and clotting disorders. We investigate the potential roles of endometrium FoxP3+ Tregs and CD56+ cells (uNK cells) and endometrial expression of PGRMC1 in the development of recurrent miscarriage. STUDY DESIGN: This prospective study included 102 out of 286 cases of SA patients. The cases were divided into groups with RM (+RM) and without RM (-RM). Immunohistochemistry staining was made using primary antibodies to FoxP3, CD56, and PGRMC1 in both groups. Morphometry analyses were carried out in 10 non-overlapping high power fields. Mann-Whitney U test, Fisher two-tail test, correlation analysis and relative risk (RR) were evaluated. A p < 0.05 was considered statistically significant. RESULTS: An increased presence of CD56-positive (p < 0.001) and FoxP3+ Treg (p = 0.0005) cells was found in the endometrium, with a reduction in PGRMC1 expression compared with -RM group (p = 0.004). A positive correlation was shown between the number of CD56-positive cells and FoxP3+ cells (r = 0.55), and an inverse correlation with PGRMC1 (r =  -0.35) in the + RM group. A similar observation was found in the -RM group, with a positive correlation of uNK cell number with the number of pregnancies (p < 0.001; r = 0.34). Endometrial infiltration of CD56-positive (p < 0.0001) and FoxP3+ (p < 0.0001) cells revealed an increased relative risk of RM. This increased risk was also revealed in SA with a loss of PGRMC1 expression (p < 0.0001). CONCLUSION: Our prospective study suggests, for the first time, that increased endometrial infiltration of uNK, FoxP3+ Treg cells and a decreased PGRMC1 expression may play potential roles in the development of RM

Perifocal Soft Tissue Reactions in Response to Contaminated Implants With a Composite Antibacterial Coating: Experimental Study

Background. Protection against microbial colonization of surface fixators for metal osteosynthesis can reduce the number of infectious complications. The aim of the study was to experimentally assess early perifocal tissue reactions to metal implants with a composite antibacterial coating under microbial load. Methods. Fragments of steel pins for osteosynthesis (diameter 1 mm) with a four-component antibacterial coating based on polylactide, polyurethane, ciprofloxacin and silver nanoparticles were contaminated by methicillin-resistant S. aureus (MRSA) 43431. They were implanted in rats within the quadriceps femoris. Contaminated uncoated pins were used as a control. The animals were withdrawn from the experiment on the 2nd, 4th, 7th day after implantation. Histopathological specimens from tissue around implants were prepared. A semiquantitative assessment of reactions was performed. Results. The microbial load before implantation was (1.120.26)106 S. aureus cells for the control implants and (0.860.31)106 cells for implants with antibacterial coating. Tissue inflammatory reactions on the second day of implantation were equally evident in the control and investigated groups. There was a significant reduction in the number of immune cells and necrotic detritus, as well as increased growth of connective tissue and neoangiogenesis in the experimental group by the 4th day. The appearance of a less pronounced well-vascularized fibrous capsule around the experimental implants was noted by the 7th day. It indicates a more favorable healing of soft tissues in comparison with the control. Conclusion. Weak morphological manifestations of tissue reactions in response to the fitting of contaminated implants with an antibacterial coating can be associated with both the direct antimicrobial effect of the coating components and the anti-inflammatory activity of silver nanoparticles and ciprofloxacin included in its composition