The Protein Secretome Is Altered in Rectal Cancer Tissue Compared to Normal Rectal Tissue, and Alterations in the Secretome Induce Enhanced Innate Immune Responses

Pătraşcu

et al. 2021

In Vivo

Background/Aim: Currently, the impact of diabetes mellitus (DM) on rectal cancer patients is complex and just partly elucidated. The purpose of this study was to investigate the impact of diabetes mellitus on rectal cancer patients focusing on tumor differentiation grade, neoadjuvant chemoradiotherapy (NACRT) response, disease-free (DFS) and overall (OS) survival. Patients and Methods: Our study's population consisted of a group of 53 patients diagnosed with locally advanced rectal cancer, who underwent NACRT, followed by radical oncological surgery. This patient population was further divided into two groups according to diabetes presence. Results: Downstaging rates, local control, DFS, and OS were lower in the DM subgroup compared to the non-DM locally advanced rectal cancer patients. Conclusion: The presence of DM at the time of diagnosis of locally advanced rectal cancer patients may be a negative predictive factor for response to neoadjuvant therapy, distant metastases, and local recurrences rates.Diabetes mellitus (DM) is one of the main chronic metabolic diseases, which have been linked to kidney, heart, and nerve damage. Currently, 422 million people worldwide have diabetes, and, despite global preventive measures, incidence and prevalence rates have been constantly increasing in the last decades (1). One of the most investigated organ-related consequences of DM is the one on kidney function (2-4), a life-threatening association if we consider the role of DM in end-stage renal disease (5).Previous retrospective studies have reported that, for other pelvic tumors (e.g. cervix uteri, bladder), amongst other irradiation response predictive factors, such as smoking status, treatment duration, radiation total dose, target volume proximity, and local anatomy, DM can also act as one of these clinically meaningful factors for the increased incidence of adverse events development (6-8). In the last decade, after an increase in colorectal cancer incidence worldwide, the connection between DM and this malignancy has been thoroughly investigated (9). There are several studies showing that patients with rectal cancer and DM have a poorer prognosis than non-DM patients (10). Although diabetic patients with rectal cancer have an inferior 2495 This article is freely accessible online.

Section: Discussionmentioning

confidence: 61%

Diabetes Mellitus as a Prognostic Factor for Locally Advanced Rectal Cancer

Pătraşcu

et al. 2021

In Vivo

“…[ [46][47][48][49][50][51][52][53][54]. Extracellular vesicles (EVs) are secreted lipid-encapsulated vesicles representing an active element of the cell secretome [55].…”

Section: Significance Statementmentioning

confidence: 99%

“…This complex mixture of proteins, lipids and nucleic acids allows for the regulation of a broad range of cellular behaviors and physiological functions. Changes in the abundance of components of the secretome are observed in many diseases, including cancer and actively shape the TME to contribute to tumor progression [46–54]. Extracellular vesicles (EVs) are secreted lipid‐encapsulated vesicles representing an active element of the cell secretome [55].…”

Section: Introductionmentioning

confidence: 99%

Cancer stem cell marker DCLK1 reprograms small extracellular vesicles toward migratory phenotype in gastric cancer cells

et al. 2021

Doublecortin-like kinase 1 (DCLK1) is a putative cancer stem cell marker, a promising diagnostic and prognostic maker for malignant tumors and a proposed driver gene for gastric cancer (GC). DCLK1 overexpression in a majority of solid cancers correlates with lymph node metastases, advanced disease and overall poor-prognosis. In cancer cells, DCLK1 expression has been shown to promote epithelial-to-mesenchymal transition (EMT), driving disruption of cell-cell adhesion, cell migration and invasion. Here, we report that DCLK1 influences small extracellular vesicle (sEV/exosome) biogenesis in a kinase-dependent manner. sEVs isolated from DCLK1 overexpressing human GC cell line MKN1 (MKN1 OE -sEVs), promote the migration of parental (non-transfected) MKN1 cells (MKN1 PAR ). Quantitative proteome analysis of MKN1 OE -sEVs revealed enrichment in migratory and adhesion regulators (STRAP, CORO1B, BCAM, COL3A, CCN1) in comparison to MKN1 PAR -sEVs. Moreover, using DCLK1-IN-1, a specific small molecule inhibitor of DCLK1, we reversed the increase in sEV size and concentration in contrast to other EV subtypes, as well as kinase-dependent cargo selection of proteins involved in EV biogenesis (KTN1, CHMP1A, MYO1G) and migration and adhesion processes (STRAP, CCN1). Our findings highlight a specific role of DCLK1-kinase dependent cargo selection for sEVs and shed new light on its role as a regulator of signaling in gastric tumorigenesis.

“…CCL22 is a chemokine that modulates immunity by increasing Treg contact with dendritic cells in lymph nodes through CCR4 receptor signaling ( 47 , 48 ). In melanoma, CCL22 boosts Treg recruitment into the TME while inhibiting anticancer immunity ( 49 ) and in colorectal adenocarcinomas, CCL22 mRNA expression is considerably higher in tumor tissue than in corresponding normal tissue ( 50 ). CCL22 is also associated with Treg and Th1 cells in CRC patients who were exposed to gut microbiota.…”

Section: Discussionmentioning

confidence: 99%

A Novel Immune-Related Gene Signature to Identify the Tumor Microenvironment and Prognose Disease Among Patients With Oral Squamous Cell Carcinoma Patients Using ssGSEA: A Bioinformatics and Biological Validation Study

et al. 2022

Oral squamous cell carcinoma (OSCC) is the most invasive oral malignancy in adults and is associated with a poor prognosis. Accurate prognostic models are urgently needed, however, knowledge of the probable mechanisms behind OSCC tumorigenesis and prognosis remain limited. The clinical importance of the interplay between the immune system and tumor microenvironment has become increasingly evident. This study explored immune-related alterations at the multi-omics level to extract accurate prognostic markers linked to the immune response and presents a more accurate landscape of the immune genomic map during OSCC. The Cancer Genome Atlas (TCGA) OSCC cohort (n = 329) was used to detect the immune infiltration pattern of OSCC and categorize patients into two immunity groups using single-sample gene set enrichment analysis (ssGSEA) and hierarchical clustering analysis. Multiple strategies, including lasso regression (LASSO), Cox proportional hazards regression, and principal component analysis (PCA) were used to screen clinically significant signatures and identify an incorporated prognosis model with robust discriminative power on the survival status of both the training and testing set. We identified two OSCC subtypes based on immunological characteristics: Immunity-high and immunity low, and verified that the categorization was accurate and repeatable. Immunity_ high cluster with a higher immunological and stromal score. 1047 differential genes (DEGs) integrate with immune genes to obtain 319 immue-related DEGs. A robust model with five signatures for OSCC patient prognosis was established. The GEO cohort (n = 97) were used to validate the risk model’s predictive value. The low-risk group had a better overall survival (OS) than the high-risk group. Significant prognostic potential for OSCC patients was found using ROC analysis and immune checkpoint gene expression was lower in the low-risk group. We also investigated at the therapeutic sensitivity of a number of frequently used chemotherapeutic drugs in patients with various risk factors. The underlying biological behavior of the OSCC cell line was preliminarily validated. This study characterizes a reliable marker of OSCC disease progression and provides a new potential target for immunotherapy against this disease.