PTEN and P-4E-BP1 might be associated with postoperative recurrence of rectal cancer patients undergoing concurrent radiochemotherapy.

BACKGROUND: Local recurrence after surgery and radiochemotherapy seriously affects the prognosis of locally advanced rectal cancer (LARC) patients. Studies on molecular markers related to the radiochemotherapy sensitivity of cancers have been widely carried out, which might provide valued information for clinicians to carry out individual treatment. AIM: To find potential biomarkers of tumors for predicting postoperative recurrence. METHODS: In this study, LARC patients undergoing surgery and concurrent radiochemotherapy were enrolled. We focused on clinicopathological factors and PTEN, SIRT1, p-4E-BP1, and pS6 protein expression assessed by immunohistochemistry in 73 rectal cancer patients with local recurrence and 76 patients without local recurrence. RESULTS: The expression of PTEN was higher, while the expression of p-4E-BP1 was lower in patients without local recurrence than in patients with local recurrence. Moreover, TNM stage, lymphatic vessel invasion (LVI), PTEN and p-4E-BP1 might be independent risk factors for local recurrence after LARC surgery combined with concurrent radiochemotherapy. CONCLUSIONS: This study suggests that PTEN and p-4E-BP1 might be potential biomarkers for prognostic prediction and therapeutic targets for LARC.

Therapy-induced senescent tumor cell-derived extracellular vesicles promote colorectal cancer progression through SERPINE1-mediated NF-κB p65 nuclear translocation.

BACKGROUND: Cellular senescence frequently occurs during anti-cancer treatment, and persistent senescent tumor cells (STCs) unfavorably promote tumor progression through paracrine secretion of the senescence-associated secretory phenotype (SASP). Extracellular vesicles (EVs) have recently emerged as a novel component of the SASP and primarily mediate the tumor-promoting effect of the SASP. Of note, the potential effect of EVs released from STCs on tumor progression remains largely unknown. METHODS: We collected tumor tissues from two cohorts of colorectal cancer (CRC) patients to examine the expression of p16, p21, and SERPINE1 before and after anti-cancer treatment. Cohort 1 included 22 patients with locally advanced rectal cancer (LARC) who received neoadjuvant therapy before surgical resection. Cohort 2 included 30 patients with metastatic CRC (mCRC) who received first-line irinotecan-contained treatment. CCK-8, transwell, wound-healing assay, and tumor xenograft experiments were carried out to determine the impacts of EVs released from STCs on CRC progression in vitro and in vivo. Quantitative proteomic analysis was applied to identify protein cargo inside EVs secreted from STCs. Immunoprecipitation and mass spectrometer identification were utilized to explore the binding partners of SERPINE1. The interaction of SERPINE1 with p65 was verified by co-immunoprecipitation, and their co-localization was confirmed by immunofluorescence. RESULTS: Chemotherapeutic agents and irradiation could potently induce senescence in CRC cells in vitro and in human CRC tissues. The more significant elevation of p16 and p21 expression in patients after anti-cancer treatment displayed shorter disease-free survival (DFS) for LARC or progression-free survival (PFS) for mCRC. We observed that compared to non-STCs, STCs released an increased number of EVs enriched in SERPINE1, which further promoted the progression of recipient cancer cells. Targeting SERPINE1 with a specific inhibitor, tiplaxtinin, markedly attenuated the tumor-promoting effect of STCs-derived EVs. Additionally, the patients with greater increment of SERPINE1 expression after anti-cancer treatment had shorter DFS for LARC or PFS for mCRC. Mechanistically, SERPINE1 bound to p65, promoting its nuclear translocation and subsequently activating the NF-κB signaling pathway. CONCLUSIONS: We provide the in vivo evidence of the clinical prognostic implications of therapy-induced senescence. Our results revealed that STCs were responsible for CRC progression by producing large amounts of EVs enriched in SERPINE1. These findings further confirm the crucial role of therapy-induced senescence in tumor progression and offer a potential therapeutic strategy for CRC treatment.

A deep neural network predictor to predict the sensitivity of neoadjuvant chemoradiotherapy in locally advanced rectal cancer.

Neoadjuvant chemoradiotherapy (NCRT) is widely used for locally advanced rectal cancer (LARC). This study aimed to conduct an effective model to predict NCRT sensitivity and provide guidance for clinical treatment. Biomarkers for NCRT sensitivity were identified by applying transcriptome profiles using logistic regression and subsequently screened out by Spearman correlation analysis and four machine learning algorithms. A deep neural network (DNN) predictor was constructed by using in-house dataset and validated in two independent datasets. Additionally, a web-based program was developed. Wnt/ß-catenin signaling and linoleic acid metabolism (LA) pathways were associated with NCRT sensitivity and prognosis in LARC, antagonistically. A DNN predictor with an 18-gene signature was conducted within in-house datasets. In two validation cohorts, area under ROC curve (AUC) achieved 0.706 and 0.897. The DNN subtypes were significantly associated with NCRT sensitivity, survival status et al. Moreover, NK and cytotoxic T cells were observed contribution to NCRT sensitivity while regulatory T, myeloid-derived suppressor cells and dysfunction of CD4 T effector memory cells could impede NCRT response. A DNN predictor could predict NCRT sensitivity in LARC and stratify LARC patients with different clinical and immunity characteristic.

Unveiling the covert interaction between gut microbiota and neutrophils to drive colorectal cancer metastasis.

The formation of the microenvironment preceding liver metastasis is intricately linked to the intestinal tract. In recent years, mounting evidence has revealed the significant involvement of neutrophil extracellular traps (NETs) in tumor metastasis, particularly in liver metastasis. Disruption of the intestinal barrier can lead to the translocation of bacteria and their metabolites, such as lipopolysaccharide, into the liver. As the primary defense against pathogens, NETs help eliminate gut-derived toxins and shape the liver's inflammatory and immunosuppressive environment. However, this double-edged sword effect can potentially stimulate tumor metastasis by creating a fertile ground for the growth of intestinal tumor cells due to impaired liver tissue and reduced activity of killer immune cells. This comprehensive review systematically describes the influence factors and mechanisms of NETs in colon cancer metastasis and explores their potential as biomarkers and therapeutic targets for liver metastasis.

The Clinical Value of Apparent Diffusion Coefficient of Readout Segmentation of Long Variable Echo Trains and Correlation With Ki-67 Expression in Distal Rectal Cancer.

OBJECTIVE: The aim of the study is to explore the clinical value of the apparent diffusion coefficient (ADC) derived from the readout segmentation of long variable echo trains (RESOLVE) technique for identifying clinicopathologic features of distal rectal cancer and correlations between ADC and Ki-67 expression. METHODS: The data of 112 patients with a proven pathology of distal rectal cancer who underwent preoperative magnetic resonance imaging were retrospectively analyzed. The mean ADC value was measured using the "full-layer and center" method. Differences in ADC values and Ki-67 expression in different clinical stages, pathological types, and tumor differentiation were compared using analysis of variance. Correlations between ADC value and clinicopathologic features were assessed using Spearman correlation analysis. RESULTS: Interobserver agreement of confidence levels from 2 radiologists was excellent for ADC measurement ( k =  0.85). Patients with a lower clinical stage, well-differentiated adenocarcinomas, and a higher possibility of mucinous adenocarcinoma exhibited a positive correlation with higher ADC values, but these factors were negatively correlated with Ki-67 expression (all P < 0.05). We found that ADC value was negatively correlated with Ki-67 expression ( r = -0.62, P < 0.001). CONCLUSIONS: The ADC value generated by RESOLVE sequences was significantly associated with clinicopathologic features and Ki-67 expression in patients with distal rectal cancer in this study. Thus, the ADC value could be considered a new noninvasive imaging biomarker that could be helpful in predicting the biological properties of distal rectal cancer.

Rectal Cancer Tissue Lipidome Differs According to Response to Neoadjuvant Therapy.

Rectal cancer (RC) is a gastrointestinal cancer with a poor prognosis. While some studies have shown metabolic reprogramming to be linked to RC development, it is difficult to define biomolecules, like lipids, that help to understand cancer progression and response to therapy. The present study investigated the relative lipid abundance in tumoral tissue associated with neoadjuvant therapy response using untargeted liquid chromatography-mass spectrometry lipidomics. Locally advanced rectal cancer (LARC) patients (n = 13), clinically staged as T3-4 were biopsied before neoadjuvant chemoradiotherapy (nCRT). Tissue samples collected before nCRT (staging) and afterwards (restaging) were analyzed to discover lipidomic differences in RC cancerous tissue from Responders (n = 7) and Non-responders (n = 6) to nCRT. The limma method was used to test differences between groups and to select relevant feature lipids from tissue samples. Simple glycosphingolipids and differences in some residues of glycerophospholipids were more abundant in the Non-responder group before and after nCRT. Oxidized glycerophospholipids were more abundant in samples of Non-responders, especially those collected after nCRT. This work identified potential lipids in tissue samples that take part in, or may explain, nCRT failure. These results could potentially provide a lipid-based explanation for nCRT response and also help in understanding the molecular basis of RC and nCRT effects on the tissue matrix.

Circulating extracellular vesicle-derived MARCKSL1 is a potential diagnostic non-invasive biomarker in metastatic colorectal cancer patients.

Extracellular vesicle-derived proteins are closely related to colorectal cancer metastasis, and early detection and diagnosis of colorectal cancer metastasis is very important to improve the prognosis. In this study, we evaluated the clinical significance of plasma EV-derived MARCKSL1 in differentiating patients with metastatic and nonmetastatic CRC. This study included 78 patients, including 40 patients with nonmetastatic colorectal cancer, 38 patients with metastatic colorectal cancer, and 15 healthy volunteers. The extracellular vesicles extracted from the participants' plasma were characterized through transmission electron microscopy, nanoparticle tracking analysis and western blotting. MARCKSL1 protein expression in the EVs was detected by ELISA, and the diagnostic efficacy of MARCKSL1 alone or in combination with CA125 and lymphocyte levels was evaluated by receiver operating characteristic curve (ROC) analysis. Pearson's correlation test was performed to detect the correlation between MARCKSL1, CA125, lymphocyte level and clinicopathological characteristics of tumors. The present study demonstrated that the level of circulating EV-derived MARCKSL1 in patients with metastatic colorectal cancer was significantly higher than that in patients with nonmetastatic colorectal cancer and healthy people. Combined with CA125 and lymphocyte levels, the best diagnostic effect was achieved, and the area under the ROC curve was 0.7480. Together, our findings indicated that circulating EV-derived MARCKSL1 could be used as a new potential diagnostic biomarker for metastatic CRC.

Modulation of rectal cancer stemness, patient outcome and therapy response by adipokines

Response to chemoradiotherapy (CRT) in patients with locally advanced rectal cancer is highly variable. Identification of CRT non-responders and definite accurate biomarkers of response are unmet needs. In turn, adipokines might impact on colorectal cancer development. We hypothesized that imbalance in leptin and adiponectin modulates stemness potential CRT response in rectal cancer. Pre-CRT serum and tissue samples were collected from a cohort of locally advanced rectal cancer patients (n = 33), submitted to long-course CRT and proctectomy. Adiponectin and leptin were measured by ELISA in serum. In tumour biopsies, mRNA expression of stemness-related genes was evaluated by qRT-PCR and transcription factor STAT3 by immunoblotting. Correlations with clinical data and accuracy of potential CRT response biomarkers were evaluated. Carcinoembryonic antigen (CEA) but not leptin or adiponectin distinguished CRT responders from non-responders (p < 0.05). However, higher leptin and lower adiponectin serum levels were associated with positive extramesorectal nodes and extramural vascular invasion. mRNA expression of stemness factors was inversely correlated with adiponectin but positively correlated with leptin. STAT3 phosphorylation presented similar results. CEA levels together with STAT3 activation and OCT4/KLF4 expression accurately identified rectal cancer patients, CRT non-responders (AUROC 0.80; p < 0.05). Adipokines might impact rectal cancer stemness and patient prognosis. The leptin/STAT3 signalling axis provides the rational for a potential biomarker panel that identifies rectal cancer patients who will not benefit from CRT treatment. (AU)

PIK3CA Mutations as a Prognostic Factor in Patients With Residual Rectal Cancer After Neoadjuvant Chemoradiotherapy.

BACKGROUND/AIM: PIK3CA mediates various cellular processes, such as transformation, tumor initiation and proliferation, and resistance to apoptosis. This study was conducted to identify the clinical significance and prognostic effect of PIK3CA mutations in patients with residual rectal cancer who underwent surgery after neoadjuvant chemoradiotherapy (NACRT). PATIENTS AND METHODS: Formalin-fixed and paraffin-embedded surgical specimens were collected from 128 patients between January 2006 and December 2011 and analyzed using real-time polymerase chain reaction for hotspot mutations in exons 9 and 20 of the PIK3CA gene. RESULTS: Of the 128 patients, 109 were analyzed and 19 were excluded because of poor DNA quality. Mutations in PIK3CA were identified in three patients (2.8%), all of which were detected in exon 20 of the PIK3CA gene. PIK3CA mutations significantly correlated with lymphatic invasion (p=0.016), lymph node metastasis (p=0.034), and higher pathological disease stage (p=0.040). By univariate analysis, patients with PIK3CA mutations were observed to have significantly shorter cancer-specific survival (CSS) (p=0.001) and disease-free survival (DFS) (p=0.006) than PIK3CA wild-type patients. However, PIK3CA mutations were not an independent prognostic factor for CSS (p=0.319) or DFS (p=0.219) in multivariate modeling. CONCLUSION: Our findings indicate that PIK3CA mutation plays a role in oncogenesis in rectal cancer and may be considered as a candidate therapeutic approach targeting the PIK3/Akt/mTOR pathway in patients with residual rectal cancer after NACRT.

Characterization of the gene signature correlated with favorable response to chemoradiotherapy in rectal cancer: A hypothesis-generating study.

PURPOSE: This study aimed to define the gene signature associated with response to neoadjuvant chemoradiotherapy (nCRT), or chemoradiosensitivity (CRS) signature, in rectal cancer, and investigate the correlation between the CRS signature and characteristics of tumor. MATERIALS AND METHODS: Three public microarray datasets of pre-nCRT rectal cancer were used to discover and validate the CRS signature, and the pathway analysis of the CRS signature was performed. Patients in The Cancer Genome Atlas (TCGA) dataset were stratified according to the CRS signature enrichment score, and mutational profile and proportions of infiltrated immune cells were compared. RESULTS: In the discovery dataset (GSE53781), 95 genes were upregulated in complete responders compared to non-complete responders and defined as the CRS signature. Pathways regarding DNA replication and repair processes as well as inflammatory response were enriched in the CRS signature. In the validation datasets (GSE35452 and GSE45404), patients with favorable response to nCRT exhibited higher enrichment score of the CRS. In TCGA-READ cohort, patients with high CRS signature harbored KRAS mutation in lower frequency than those with low CRS signature. In addition, proportions of proinflammatory immune cells were higher, but proportion of immunosuppressive M2 macrophages was lower in patients with high CRS signature than those with low CRS signature. CONCLUSIONS: The current integrative bioinformatic analysis suggests the CRS signature and showed that the CRS signature is associated with dissimilar mutational profile and increased immune response. The discovered CRS signature and related characteristics may serve as candidate of stratification factor in upcoming studies for rectal cancer.

Serum CCL7 Is a Novel Prognostic Biomarker of Metastatic Colorectal Cancer.

BACKGROUND/AIM: Colorectal cancer is the third most common cancer globally, and the poor prognosis of patients with metastatic colorectal cancer (mCRC) warrants urgent attention. We previously obtained 10 candidate serum biomarkers for mCRC. Our aim with this study was to determine the prognostic performance of the pre-treatment serum C-C motif chemokine ligand 7 (CCL7) concentration in patients with mCRC. PATIENTS AND METHODS: Protein concentrations of CCL7 were examined using ELISA and immunohistochemistry for serum (n=110) and surgical specimens (n=85), respectively, of patients with mCRC. The relationship between protein concentration and prognosis was examined using Cox regression analysis, receiver operator characteristic curve analysis and the Kaplan-Meier method. RESULTS: The overall survival (OS) of patients with high concentrations of serum CCL7 was significantly poorer than that of patients with low concentrations. Patients with a high CCL7 concentration in the stroma had significantly poorer outcomes than those with a low concentration. The concentrations of carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 were significantly higher in the high-CCL7 group, compared to those in the low-CCL7 group. Univariate and multivariate analysis revealed that serum CCL7 concentration was a significant prognostic factor for mCRC. The combination of serum CCL and CEA concentrations was also useful in this regard (area under the curve=0.71). CONCLUSION: The combined pre-treatment serum levels of CCL7 and CEA are useful prognostic biomarkers for mCRC.

Modulation of rectal cancer stemness, patient outcome and therapy response by adipokines.

Response to chemoradiotherapy (CRT) in patients with locally advanced rectal cancer is highly variable. Identification of CRT non-responders and definite accurate biomarkers of response are unmet needs. In turn, adipokines might impact on colorectal cancer development. We hypothesized that imbalance in leptin and adiponectin modulates stemness potential CRT response in rectal cancer. Pre-CRT serum and tissue samples were collected from a cohort of locally advanced rectal cancer patients (n = 33), submitted to long-course CRT and proctectomy. Adiponectin and leptin were measured by ELISA in serum. In tumour biopsies, mRNA expression of stemness-related genes was evaluated by qRT-PCR and transcription factor STAT3 by immunoblotting. Correlations with clinical data and accuracy of potential CRT response biomarkers were evaluated. Carcinoembryonic antigen (CEA) but not leptin or adiponectin distinguished CRT responders from non-responders (p < 0.05). However, higher leptin and lower adiponectin serum levels were associated with positive extramesorectal nodes and extramural vascular invasion. mRNA expression of stemness factors was inversely correlated with adiponectin but positively correlated with leptin. STAT3 phosphorylation presented similar results. CEA levels together with STAT3 activation and OCT4/KLF4 expression accurately identified rectal cancer patients, CRT non-responders (AUROC 0.80; p < 0.05). Adipokines might impact rectal cancer stemness and patient prognosis. The leptin/STAT3 signalling axis provides the rational for a potential biomarker panel that identifies rectal cancer patients who will not benefit from CRT treatment.

Pilot proteomic study of locally advanced rectal cancer before and after neoadjuvant chemoradiotherapy indicates high metabolic activity in non-responders' tumor tissue.

PURPOSE: In the search for candidate predictive biomarkers to evaluate response to neoadjuvant chemoradiotherapy (nCRT) in rectal cancer, only a few studies report proteomic profiles of tumor tissue before and after nCRT. The aim of our study was to determine differentially expressed proteins between responders and non-responders before and after the therapy in order to identify candidate molecules for prediction and follow-up of response to nCRT. EXPERIMENTAL DESIGN: The study has included tissue sections of rectal tumor and non-tumor mucosa from five responders and five non-responders taken before and after nCRT from patients with locally advanced rectal cancer. Extracted proteins were analyzed by LC-MS/MS analysis followed by a set of bioinformatics analyses. RESULT: Proteomics analysis provided a mean of approximately 1050 protein identifications per sample. A comparison of proteomic profiles between responders and non-responders has identified 18 differentially expressed proteins. Pathway analysis demonstrated high metabolic activity in non-responders' tumors before nCRT, indicating the presence of intrinsic chemoradioresistance in these subjects. Two proteins associated with poor prognosis in colorectal cancer, ADAM10 and CAD, were identified as candidate predictive biomarkers as they were present in non-responders only. CONCLUSIONS AND CLINICAL RELEVANCE: Shortlisted proteins from our study should be further validated as candidate biomarkers for response to routinely applied nCRT protocols.

The recovery of intestinal barrier function and changes in oral microbiota after radiation therapy injury.

Introduction: Colorectal cancer (CRC) is the third most common malignant tumor, and neoadjuvant chemo-radiotherapy is usually recommended for advanced stage colorectal cancer. Radiotherapy can cause damage to intestinal mucosal barrier, which may be related to perioperative complications. Intestinal microbiota is one of the constituents of the intestinal mucosal biological barrier, and literature reports that patients with CRC have changes in corresponding oral microbiota. This study aims to analyze the levels of immunoglobulin SIgA, inflammatory factors, lymphocyte subsets quantity, and proportion in surgical specimens of intestinal mucosa at different time intervals after radiotherapy, in order to seek investigation for the optimal surgical time after radiotherapy and to provide evidence for finding probiotics or immunomodulators through high-throughput sequencing of bacterial 16s rRNA in patients' saliva microbiota. Ultimately, this may provide new ideas for reducing perioperative complications caused by radiotherapy-induced intestinal damage. Methods: We selected intestinal mucosal tissue and saliva samples from over 40 patients in our center who did not undergo radiotherapy and underwent surgery at different time intervals after radiotherapy. Detection of SIgA was performed using ELISA assay. Western Blotting was used to detect IL-1ß, IL-6, and IL-17 in the intestinal mucosal tissue. Flow cytometry was used to detect CD4 and CD8. And the microbial community changes in saliva samples were detected through 16s rRNA sequencing. Results: After radiotherapy, changes in SIgA, various cytokines, CD4CD8 lymphocyte subsets, and oral microbiota in the intestinal mucosal tissue of rectal cancer patients may occur. Over time, this change may gradually recover. Discussion: In colorectal cancer, oncological aspects often receive more attention, while studies focusing on the intestinal mucosal barrier are less common. This study aims to understand the repair mechanisms of the intestinal mucosal barrier and reduce complications arising from radiotherapy-induced damage. The relationship between oral microbiota and systemic diseases has gained interest in recent years. However, the literature on the oral microbiota after radiotherapy for rectal cancer remains scarce. This study addresses this gap by analysing changes in the salivary microbiota of rectal cancer patients before and after radiotherapy, shedding light on microbiota changes. It aims to lay the groundwork for identifying suitable probiotics or immunomodulators to alleviate perioperative complications and improve the prognosis of CRC.

Clinical impact of lymphocyte/C-reactive protein ratio on postoperative outcomes in patients with rectal cancer who underwent curative resection.

Cancer-related systemic inflammation influences postoperative outcomes in cancer patients. Although the relationship between inflammation-related markers and postoperative outcomes have been investigated in many studies, their clinical significance remains to be elucidated in rectal cancer patients. We focused on the lymphocyte count/C-reactive protein ratio (LCR) and its usefulness in predicting short- and long-term outcomes after rectal cancer surgery. Patients with rectal cancer who underwent curative resection at our institution between 2010 and 2018 were enrolled in this study. We comprehensively compared the effectiveness of 11 inflammation-related markers, including LCR and other clinicopathological characteristics, in predicting postoperative complications and survival. Receiver operating characteristic curve analysis indicated that LCR had the highest area under the curve value for predicting the occurrence of postoperative complications. In the multivariate analysis, male sex (odds ratio [OR]: 2.21, 95% confidence interval [CI] 1.07-4.57, P = 0.031), low tumor location (OR: 2.44, 95% CI 1.23-4.88, P = 0.011), and low LCR (OR: 3.51, 95% CI 1.63-7.58, P = 0.001) were significantly and independently associated with the occurrence of postoperative complications. In addition, multivariate analysis using Cox's proportional hazard regression model for the prediction of survival showed that low LCR (≤ 12,600) was significantly associated with both poor overall survival (hazard ratio [HR]: 2.07, 95% CI 1.03-4.15, P = 0.041) and recurrence-free survival (HR: 2.21, 95% CI 1.22-4.01, P = 0.009). LCR is a useful marker for predicting both short- and long-term postoperative outcomes in rectal cancer patients who underwent curative surgery.

The role of the PTEN/mTOR axis in clinical response of rectal cancer patients.

BACKGROUND: Preoperative chemoradiotherapy has long been accepted as a method to improve survival and lifetime quality of rectal cancer patients. However, physiologic effects of these therapies largely depend on the resistance of cells to the radiation, type of chemotherapeutic agents and individual responses. As one of the signaling cascades involved in chemo- or radiation- resistance, the present study focused on several proteins involved in pTEN/Akt/mTOR pathway to explore their prognostic significance. MATERIALS AND METHODS: Samples from advanced stage rectal cancer patients were analyzed to detect expression levels of pTEN/Akt/mTOR pathway related proteins pTEN, mLST8, REDD1, BNIP3, SAG and NOXA, together with p53, by RT-qPCR. Kaplan-Meier analysis was used to assess expression-survival relation and correlations among all proteins and clinicopathological features were statistically analyzed. RESULTS: Except p53, none of the proteins showed prognostic significance. High p53 expression presented clear impact on overall survival and disease free survival. It was also significantly related to pathologic complete response. p53 showed high correlation to local recurrence as well. On the other hand, strong correlation was observed with PTEN expression and tumor response, but not with survival. High associations were also observed between mLST8/REDD1, PTEN and NOXA, confirming their role in the same cascade. CONCLUSION: The contentious role of p53 as a prognostic biomarker in colorectal cancer was further affirmed, while PTEN and REDD1 could be suggested as potential candidates. Additionally, NOXA emerges as a conjunctive element for different signaling pathways.

Tissue-Based Markers as a Tool to Assess Response to Neoadjuvant Radiotherapy in Rectal Cancer-Systematic Review.

According to current guidelines, the current treatment for locally advanced rectal cancer is neoadjuvant therapy, followed by a total mesorectal excision. However, radiosensitivity tends to differ among patients due to tumor heterogeneity, making it difficult to predict the possible outcomes of the neoadjuvant therapy. This review aims to investigate different types of tissue-based biomarkers and their capability of predicting tumor response to neoadjuvant therapy in patients with locally advanced rectal cancer. We identified 169 abstracts in NCBI PubMed, selected 48 reports considered to meet inclusion criteria and performed this systematic review. Multiple classes of molecular biomarkers, such as proteins, DNA, micro-RNA or tumor immune microenvironment, were studied as potential predictors for rectal cancer response; nonetheless, no literature to date has provided enough sufficient evidence for any of them to be introduced into clinical practice.

Expression profile and prognostic significance of HOXB13 in rectal cancer.

BACKGROUND: This study aimed to investigate the expression pattern and prognostic significance of HOXB13 in rectal cancer. METHODS: HOXB13 expression in rectal cancer and normal adjacent tissues was detected by reverse transcriptase-polymerase chain reaction and immunohistochemistry, and its clinicopathological characteristics and prognosis were statistically tested. Furthermore, we evaluated the association between tumor immune infiltrating cells and HOXB13 using the tumor immune estimation resource (TIMER) database. The potential biological mechanism associated with HOXB13 overexpression was investigated by gene set enrichment analysis (GSEA). RESULTS: The expression of HOXB13 messenger RNA and protein in human rectal cancer tissues were significantly higher than those in the normal adjacent tissues (P < 0.05). HOXB13 expression was significantly correlated with depth of invasion, lymphatic invasion, lymph node metastasis, distant metastasis, and pathological tumor node metastasis stage (P < 0.05). Kaplan-Meier survival curves confirmed that HOXB13 overexpression was correlated negatively with overall survival and disease-free survival in rectal cancer (P < 0.05). Also, multivariate Cox regression analysis demonstrated that HOXB13 expression, age, and lymphatic invasion were independent prognostic factors in rectal cancer (P < 0.05). Plus, the results from the TIMER database indicated that HOXB13 expression has a significant association with several immune cell infiltrates. Finally, the GSEA results indicated that HOXB13 participated in the various immune-associated processes, including natural killer cell-mediated cytotoxicity and the T-cell receptor signaling pathway. CONCLUSION: Our study showed an essential role of HOXB13 in rectal cancer immunity and prognosis. Significantly, the overexpression of HOXB13 leads to the worse prognosis for patients with rectal cancer, which will contribute to understanding molecular mechanisms associated with tumor pathogenesis and prognosis in this disease.

The Prognostic Value of FoxP3+ Tumour-Infiltrating Lymphocytes in Rectal Cancer Depends on Immune Phenotypes Defined by CD8+ Cytotoxic T Cell Density.

Tumour-infiltrating FoxP3+ regulatory T cells have been identified as both positive and negative prognostic factors in colorectal cancer (CRC) and rectal cancer (RC). In this study we investigated whether immune phenotypes, defined by CD8+ cytotoxic T cell density, may influence the prognostic association of FoxP3+ T cell densities in RC. Tissue microarrays from 154 rectal cancer resections were immunohistochemically double stained for CD8 and FoxP3. CD8+ and FoxP3+ cell densities were measured in the stromal and intraepithelial compartment. Stromal FoxP3+ cell densities were not associated with 10-year overall survival (OS). In the "immune-desert" phenotype, defined by very low stromal CD8+ cell density, a high density of stromal FoxP3+ T cells displayed a tendency towards an association with decreased 10-year OS (p = 0.179). In "inflamed" tumours, defined by high intraepithelial CD8+ T cell infiltration, the opposite was the case and high stromal FoxP3+ T cell densities were a positive prognostic factor (p = 0.048). Additionally, patients with an increased FoxP3/CD8 cell density ratio demonstrated a strong trend towards decreased 10-year OS (p = 0.066). These contrasting findings suggest functional heterogeneity within the group of FoxP3+ T cells. They are consistent with experimental studies which reported suppressive and non-suppressive populations of FoxP3+ T cells in CRC. Furthermore, our study demonstrates that CD8 immunohistochemistry may act as an instrument to identify tumours infiltrated by possibly functionally differing FoxP3+ T cell subtypes.

Inflammatory fibroblasts mediate resistance to neoadjuvant therapy in rectal cancer.

Standard cancer therapy targets tumor cells without considering possible damage on the tumor microenvironment that could impair therapy response. In rectal cancer patients we find that inflammatory cancer-associated fibroblasts (iCAFs) are associated with poor chemoradiotherapy response. Employing a murine rectal cancer model or patient-derived tumor organoids and primary stroma cells, we show that, upon irradiation, interleukin-1α (IL-1α) not only polarizes cancer-associated fibroblasts toward the inflammatory phenotype but also triggers oxidative DNA damage, thereby predisposing iCAFs to p53-mediated therapy-induced senescence, which in turn results in chemoradiotherapy resistance and disease progression. Consistently, IL-1 inhibition, prevention of iCAFs senescence, or senolytic therapy sensitizes mice to irradiation, while lower IL-1 receptor antagonist serum levels in rectal patients correlate with poor prognosis. Collectively, we unravel a critical role for iCAFs in rectal cancer therapy resistance and identify IL-1 signaling as an attractive target for stroma-repolarization and prevention of cancer-associated fibroblasts senescence.