Introduction

Immune checkpoint blockade (ICB) for treatment of colorectal cancer (CRC) has been approved for clinical use since 2017. However, the approval of PD-L1 inhibitor for CRC has been encumbered by the lack of durable clinical benefits. Increasing evidence from other cancer types support that PD-L1 expression correlates to the efficacy of ICB and tumor PD-L1 is essential for ICB-mediated tumor cytotoxicity [1-3]. Concomitantly, many studies have also demonstrated the infrequent expression of PD-L1 in CRC cells [4, 5], thereby alluding to the possibility of low/absent PD-L1 expression as a primary obstacle to ICB efficacy.

Aims & Methods

Given the integral role of tumour microenvironment (TME) in shaping the tumour’s natural history, we sought to elucidate the role of tumour stroma in regulating CRC PD-L1 expression. To this end, we aim to rescue tumor PD-L1 and assess its utility in ICB-mediated anti-tumour immunity.
​To explore the role of different cell types in the TME on CRC PD-L1 expression, cocultures between major cell compartments of the TME and CRC cell lines were performed. Further various omics approaches were utilised to characterise the crosstalk between CRC and stromal cells that saw significant suppression of CRC PD-L1 expression.

Results

Myeloid cells are able to exert a significant suppression of PD-L1 expression in CRC and this suppression is regulated at a post-transcriptional level. The underlying mechanism is orchestrated by CRC metabolic shift from glycolysis to oxidative phosphorylation in response to harsh metabolic competition within the TME.

Conclusion

We have identified potential cellular compartment of the TME and mechanisms which may explain, in part, low/absent CRC PD-L1 expression. This can thus serve to evaluate appropriate external manipulations that can alleviate CRC PD-L1 suppression and explore the possibility of combinatory therapy with anti-PD-L1 ICB to improve its clinical efficacy and durability.

References

1. Herbst, R.S., et al., Atezolizumab for First-Line Treatment of PD-L1–Selected Patients with NSCLC. New England Journal of Medicine, 2020. 383(14): p. 1328-1339.
2. Cortes, J., et al., Pembrolizumab plus Chemotherapy in Advanced Triple-Negative Breast Cancer. New England Journal of Medicine, 2022. 387(3): p. 217-226.
3. Lau, J., et al., Tumour and host cell PD-L1 is required to mediate suppression of anti-tumour immunity in mice. Nature Communications, 2017. 8(1): p. 14572.
4. Llosa, N.J., et al., The Vigorous Immune Microenvironment of Microsatellite Instable Colon Cancer Is Balanced by Multiple Counter-Inhibitory Checkpoints. Cancer Discovery, 2015. 5(1): p. 43-51.
5. Taube, J.M., et al., Association of PD-1, PD-1 Ligands, and Other Features of the Tumor Immune Microenvironment with Response to Anti–PD-1 Therapy. Clinical Cancer Research, 2014. 20(19): p. 5064-5074.

Introduction

The incidence of early-stage colorectal cancer (CRC) rises with the introduction of colorectal screening programs; there is a shift towards less invasive treatment in screen-detected compared to non-screen-detected CRCs.

Aims & Methods

This retrospective, single-center cohort study aimed to assess the impact of colorectal screening on the incidence of submucosal invasive (pT1) CRC and compare treatment characteristics of screen-detected and non-screen-detected lesions between 2010 and 2023.
Screen-detected pT1 CRC (involving lesions detected with the pilot CRC screening in Csongrád-Csanád county in 2015, and those with the Hungarian population-based screening program [EFOP-1.8.1-VEKOP-15-2016-00001] initiated in 2019) lesion, patient and treatment characteristics were compared to pT1 lesions detected outside the screening program in average-risk patients aged 50-70 years during the screening period (2015-2016 and 2019-2023). The impact of screening on pT1 CRC incidence was assessed with investigating new pT1 CRC cases throughout the screening period (2015-2016 and 2019-2023) compared to non-screening periods (2010-2014 and 2017-2018).

Results

During the 14-year study period, a total of 182 pT1 CRCs were detected in average-risk patients aged 50-70 years. 81 of these lesions (44.5%) were detected during non-screening periods. During the screening period, 44 lesions were screen-detected (24.2%, 16 of these detected during the pilot screening) and 57 lesions were non-screen-detected (31.3%). Mean pT1 incidence was higher in the screening than in the non-screening periods (14.7 vs. 11.6 lesions/year, p<0.01); with the highest incidence during the pilot screening (2015-2016; 20 lesions/year), and the lowest during the pandemic (2020-2021, 9 lesions/year).
Patient and lesion characteristics were similar in screen-detected and non-screen-detected lesions (mean age: 63.1 vs 63.5 years, male ratio: 62.8% vs 64.3%, follow-up period: 3.85 vs 3.70 years; location: 31.8% vs 33.3% rectal, morphology: 34.1% vs 42.1% pedunculated, mean lesion size: 21.0 vs 24.7 mm). No difference in histologic prognostic factors were found between the two groups. Treatment choices were similar for both screen-detected, and non-screen-detected lesions: local excision in 65.9% vs 72.2% (incl. ER in 63.6% vs 63.2%, and minimally invasive local surgical resection in 2.3% vs 7.0%), and surgical oncologic resection in 34.1% vs 29.8%, respectively; p=0.167. Screen-detected colon cancers were more likely to be treated with surgical oncologic resection (43.3% vs 28.9%, p=0.218), while screen-detected rectal cancers were preferred to be treated with local excision (85.7% vs 68.4% [ER: 78.6% vs 47.4%], p=0.416) compared to non-screen-detected lesions.
During the follow-up, adverse outcomes (local recurrence and/or dissemination) occurred in two screen-detected, and in one non-screen-detected patient, p=0.797. Lymph node involvement rate was similar in those undergoing surgical oncologic resection in screen-detected, and non-screen-detected patients (6.7% vs 5.9%, respectively; p=0.927).

Conclusion

The incidence of submucosally invasive CRC rises with the implementation of colorectal screening program. There is no difference in the management and outcomes of screen-detected and non-screen-detected pT1 CRCs, but local excision, especially endoscopic resection is preferred for screen-detected rectal lesions.

Introduction

One of major obstacles of treatment in colorectal cancer (CRC) is drug resistance, specially 5-Fu chemoresistance which is a fundamental drug in CRC chemotherapy. Also, there is no reliable biomarkers in order to identify chemoresistance patients and improve their treatment. There are several factors that cause 5-FU chemoresistance include autophagy. This cell death phenomenon is played key role in 5-FU chemoresistance in CRC patients by providing nutritarians for CRC cells in hard circumstances; also, autophagy has regulated by different factors like genes and non-coding RNAs(ncRNA).

Aims & Methods

Verifying key gene in autophagy pathway at KEGG database. Moreover, evaluation the expression of key gene in CRC patients at TCGA database. Investigation on the key gene related LncRNAs and miRNAs in CRC at LNCpedia and mirTARBase database respectively, in order to find most relevant ncRNAs of this gene and obtain proper biomarkers. Developing 5-FU chemoresistance Caco2 and SW480 cell lines by increasing dosage of drug and MTT assay was performed to confirm the chemoresistance cell lines and western blot was performed to confirm autophagy in cell lines. Finally, evaluating the expression of MAP1LC3A and its related ncRNAs in 5-FU chemoresistant CRC cell lines by qRT-PCR.

Results

MAP1LC3A was confirmed as key gene based on KEGG analysis; also, FAM225A, NCK1-DT, LINC01825, LINC02188 and miR-335-5p have nominated as most relevant ncRNAs based on bioinformatic analysis. Furthermore, qRT-PCR analysis of MAP1LC3A and its related ncRNAs have shown differential expression between chemoresistant and chemoresistant CRC cell lines.

Conclusion

These findings indicate that FAM225A, NCK1-DT, LINC01825, LINC02188 and miR-335-5p participate in autophagy by effecting the expression of MAP1LC3A gene and they can function as proper biomarkers for 5-FU chemoresistance CRC patients. Not only they can function as biomarkers but also, they can attend in target therapy by designing siRNAs to knockdown this ncRNAs and enhance chemotherapy in CRC patients.

Introduction

Colorectal cancer (CRC) is one of the most common malignancies worldwide, and early detection significantly improves patient outcomes. Long non-coding RNAs (lncRNAs) are >200 nucleotide transcripts that regulate gene expression and are frequently dysregulated in cancer. Notably, certain lncRNAs are overexpressed during colorectal tumorigenesis and detectable in circulation, making them promising non-invasive biomarkers. This study aimed to identify circulating lncRNAs with progressive expression changes along the adenoma-carcinoma sequence and evaluate their potential as early diagnostic markers for CRC.

Aims & Methods

We performed bioinformatic screening of three public gene expression datasets (GSE117606, GSE289499, GSE154548) containing colorectal normal, adenoma, and carcinoma tissues. Twelve lncRNA candidates showing linear differential expression across the adenoma-to-carcinoma sequence were identified. The five most significantly dysregulated lncRNAs (ZFAS1, FOXP4-AS1, CRNDE, UCA1, SNHG17) were selected for further validation. Plasma samples were collected from healthy controls (n=21), patients with advanced adenomas (precancerous lesions, n=51), early-stage CRC (Tis-T1, n=24), and advanced CRC (T2-T4, n=53). Levels of the five lncRNAs in plasma were measured by quantitative PCR and normalized to 5S rRNA using the 2^-ΔCt method. Expression trends across the four groups were analyzed. Receiver operating characteristic (ROC) curves (area under the curve, AUC) were generated to assess the ability of individual lncRNAs to distinguish early CRC from controls. A logistic regression model was used to combine multiple lncRNAs into a panel and evaluate its diagnostic performance (sensitivity and specificity).

Results

Bioinformatic analysis identified 12 lncRNAs with stepwise expression changes from adenoma to carcinoma, and the top five candidates were successfully measured in plasma. Among these, UCA1 and SNHG17 showed progressively increasing plasma levels from healthy controls to adenoma to early CRC, with the highest levels in advanced CRC (trend P<0.05). In contrast, CRNDE levels remained unchanged between healthy and early CRC groups but rose significantly in advanced CRC, suggesting its upregulation is associated with tumor progression. The other two lncRNAs (ZFAS1, FOXP4-AS1) exhibited less pronounced changes. In diagnostic tests, UCA1 alone distinguished early-stage CRC from controls with an AUC of 0.82, whereas SNHG17 achieved an AUC of 0.73. Notably, a combined three-lncRNA panel (UCA1 + SNHG17 + CRNDE) improved early CRC detection, achieving an AUC of 0.85 with 87.5% sensitivity and 61.9% specificity for differentiating early CRC from healthy individuals. This multi-marker panel outperformed any single lncRNA biomarker in identifying early CRC.

Conclusion

A GEO dataset-guided approach coupled with plasma validation provided robust evidence that circulating lncRNAs have significant diagnostic potential for CRC. UCA1 and SNHG17 emerged as promising blood-based markers for early detection of colorectal neoplasia, while CRNDE may serve as a complementary marker indicative of advanced disease progression. Moreover, a panel combining these lncRNAs demonstrated superior accuracy over individual markers, underscoring the value of a multi-lncRNA approach. These findings support further development of non-invasive, lncRNA-based blood tests for early colorectal cancer screening.

Introduction

Colorectal cancer (CRC) remains a significant public health concern, with its incidence steadily rising worldwide. Despite notable strides in treatment modalities, predicting disease progression and tailoring therapeutic approaches remains a challenge. In this context, identifying reliable and simple prognostic factors is crucial for optimizing disease outcomes.

Aims & Methods

The aim of this study was to investigate the predictive and prognostic value of C-reactive protein-to-albumin ratio (CAR) in CRC. We conducted a retrospective and descriptive study including patients diagnosed with primary colon or rectal cancer, over an 8-year period [January 2014-June 2022]. Patient demographics, inflammatory markers, tumor characteristics, treatment and follow-up data were collected. Baseline CAR was calculated for each patient. Data were entered and analyzed by SPSS software version 26.

Results

Sixty-five patients were included, with a mean age at disease diagnosis of 61 ± 14 years and a sex ratio M/F=1.82. The median level of CAR was 0.4 [0.1-1.3]. No significant association was noted of CAR neither with age of disease onset (p=0.26), nor gender (p=0.86), nor smoking (p=0.88) nor family history of CRC (p= 0.54). For biological data, high levels of carcinoembryonic antigen and CA19-9 were significantly associated with a higher level of CAR (p=0.002 and p=0.01 respectively). We noted a significant association between lower levels of CAR and hematochezia (p=0.01) and so, rectal tumors were associated with lower levels of CAR compared with colonic tumors (26.2 vs 36; p=0.05). Circumferential, stenoting and friable tumors with hemorrhagic appearance were significantly associated with higher CAR levels (p=0.01; p=0.001 and p=0.01 respectively). We noted a significant association between high levels of CAR and metastases (50.1 vs 29.8; p=0.002) and mainly hepatic metastases (p=0.004). Regarding treatment, neither primary surgery nor urgent surgery nor adjuvant chemotherapy were associated with CAR (p=0.11; p=0.12 and p=0.85 respectively). However, an increased CAR was significantly associated with early readmission within 30 days subsequent to surgery (41.3 vs 26.7; p=0.01). Lower overall survival was associated with higher CAR rates (38.8 vs 29; p=0.04). Area under the receiver operating characteristic curve analysis showed that higher CAR was predictive of a shorter progression-free survival (AUROC = 0.65). The optimal cutoff value was 0.3 (sensitivity, 70%; specificity, 62%). A total of 36 (55%) patients had a CAR above this threshold. These patients presented more frequently with lymphopenia (p=0.03) and higher carcinoembryonic antigen rates (p=0.02). We noted no association between advanced TNM stage 3 or 4 and CAR levels, regardless of this threshold (p=0.36), and overall disease recurrence was similar for CAR above and below 0.3 (p=0.46).

Conclusion

C-reactive protein-to-albumin ratio is a strong predictor of progression-free survival and is associated with clinicopathological factors in CRC. It serves as a valuable tool for straightforward prognostic assessment, aiding in more personalized treatment decisions.

Introduction

Colorectal cancer (CRC) is one of the most common digestive tract malignant tumors, and its incidence rate and mortality rate rank third among all malignant tumors. The IMMUNOGLOBULIN SUPERFAMILY DOMAINS genes has been reported to be hypermethylated in human colorectal cancer (CRC) cell lines and primary tumor tissues, .On the other hand High mobility group genes are characteristically present at high levels in a variety of human cancers including colorectal, ovarian, breast, lung, and pancreatic cancer.

Aims & Methods

The aim of the work to evaluate the gene expression of both leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) (as an example of immunoglobulin sperfamily domains and High mobility group AT-hook 2 (HMGA2) as an example of high mobility group as diagnostic and prognostic markers in cases of colorectal cancer.
In this study forty-five patients pathologically approved with colorectal cancer were prospectively analyzed for LRIG1 and HMGA2 genes expression at tissue level. SYBR Green Real-Time RT-PCR technique was used for gene expression analyses and β-actin gene was considered as a reference gene for data normalization. Additionally, appropriate statistical analyses were used to assess the expression of LRIG1 and HMGA2 in diseased and adjacent healthy tissues.

Results

HMGA2 mRNA gene expression was over-expressed in CRC tissue than normal tissue ( median fold change and median Log² ratio are [9.3(0.2, 100.4) and 3.1(-2.6, 6.7), respectively]with positive correlation between HMGA2 and poor differentiation ,more advanced stage and lymph node metastasis(p> 0.05) but not with distant metastasis (p >0.05) , The expression of LRIG1 mRNA gene in tumor tissue was low expressed in colorectal tumor tissues (Median fold change and median Log2 ratio are [0.29(0.01, 4.14) and -1.8(-6.1, 2.1), respectively but no correlation of the LRIG1 gene with the the stage, Differentiation and metastasis of the CRC (P >0.05). There is no correlation of both genes neither with tumor biomarkers (CA19-9, CEA) nor with laboratory findings (WBCs, Hemoglobin, Platelet, INR, Albumin, Creatinine) P>0.5%). The overall survival showed no significant association with any genetic expression of both genes (P >0.05).

Conclusion

LRIG1 low expression may be considered for diagnosis but not valuable as prognostic marker in colorectal cancer patients. However, HMGA2 overexpression may be valuable as both diagnostic and prognostic markers in CRC.

Disclosure

No conflict of interest to be disclosed