Colon Tumor Research Articles

Sex differences in colonic gene expression and fecal microbiota composition in a mouse model of obesity-associated colorectal cancer

This study investigated the sex-specific correlation between obesity and colorectal cancer emphasizing a more pronounced association in males. Estrogen, chromosomal genes, and gut bacteria were assessed in C57BL6/J male, female and ovariectomized (OVX) female mice, subjected to either a low-fat diet (LFD) or high-fat diet (HFD) for 14 weeks. Induction of colon tumor involved azoxymethane (10 mg/kg) administration, followed by three cycles of dextran sulfate sodium. Male mice on HFD exhibited higher final body weight and increased colon tumors compared to females. Colonic mucin 2 expression was significantly higher in females. HFD-modulated differentially expressed genes numbered 290 for males, 64 for females, and 137 for OVX females. Only one up-regulated gene (Gfra3) overlapped between females and OVX females, while two down-regulated genes (Thrsp and Gbp11) overlapped between males and OVX females. Genes up-regulated by HFD in males were linked to cytokine-cytokine interaction, HIF-1 signaling pathway, central carbon metabolism in cancer. Sex-specific changes in gut microbial composition in response to HFD were observed. These findings suggest a male-specific vulnerability to HFD-induced colon tumor formation, implicating key genes and colonic bacteria in colon tumorigenesis.

The dopamine transporter antagonist vanoxerine inhibits G9a and suppresses cancer stem cell functions in colon tumors.

Cancer stem cells (CSCs), functionally characterized by self-renewal and tumor-initiating activity, contribute to decreased tumor immunogenicity, while fostering tumor growth and metastasis. Targeting G9a histone methyltransferase (HMTase) effectively blocks CSC functions in colorectal tumors by altering pluripotent-like molecular networks; however, existing molecules directly targeting G9a HMTase activity failed to reach clinical stages due to safety concerns. Using a stem cell-based phenotypic drug-screening pipeline, we identified the dopamine transporter (DAT) antagonist vanoxerine, a compound with previously demonstrated clinical safety, as a cancer-specific downregulator of G9a expression. Here we show that gene silencing and chemical antagonism of DAT impede colorectal CSC functions by repressing G9a expression. Antagonizing DAT also enhanced tumor lymphocytic infiltration by activating endogenous transposable elements and type-I interferon response. Our study unveils the direct implication of the DAT-G9a axis in the maintenance of CSC populations and an approach to improve antitumor immune response in colon tumors.

Manipulating Redox Homeostasis of Cancer Stem Cells Overcome Chemotherapeutic Resistance through Photoactivatable Biomimetic Nanodiscs.

Tumor heterogeneity remains a significant obstacle in cancer therapy due to diverse cells with varying treatment responses. Cancer stem-like cells (CSCs) contribute significantly to intratumor heterogeneity, characterized by high tumorigenicity and chemoresistance. CSCs reside in the depth of the tumor, possessing low reactive oxygen species (ROS) levels and robust antioxidant defense systems to maintain self-renewal and stemness. A nanotherapeutic strategy is developed using tumor-penetrating peptide iRGD-modified high-density lipoprotein (HDL)-mimetic nanodiscs (IPCND) that ingeniously loaded with pyropheophorbide-a (Ppa), bis (2-hydroxyethyl) disulfide (S-S), and camptothecin (CPT) by synthesizing two amphiphilic drug-conjugated sphingomyelin derivatives. Photoactivatable Ppa can generate massive ROS which as intracellular signaling molecules effectively shut down self-renewal and trigger differentiation of the CSCs, while S-S is utilized to deplete GSH and sustainably imbalance redox homeostasis by reducing ROS clearance. Simultaneously, the depletion of GSH is accompanied by the release of CPT, which leads to subsequent cell death. This dual strategy successfully disturbed the redox equilibrium of CSCs, prompting their differentiation and boosting the ability of CPT to kill CSCs upon laser irradiation. Additionally, it demonstrated a synergistic anti-cancer effect by concurrently eliminating therapeutically resistant CSCs and bulk tumor cells, effectively suppressing tumor growth in CSC-enriched heterogeneous colon tumor mouse models.

Delivery of Interferon β-Encoding Plasmid via Lipid Nanoparticle Restores Interferon β Expression to Enhance Antitumor Immunity in Colon Cancer.

Type I interferon (IFN-I) plays a critical role in host cancer immunosurveillance, but its expression is often impaired in the tumor microenvironment. We aimed at testing the hypothesis that cationic lipid nanoparticle delivery of interferon β (IFNβ)-encoding plasmid to tumors is effective in restoring IFNβ expression to suppress tumor immune evasion. We determined that IFN-I function in tumor suppression depends on the host immune cells. IFN-I activates the expression of Cxcl9 and Cxcl10 to enhance T cell tumor infiltration. RNA-Seq detected a low level of IFNα13 and IFNβ in colon tumor tissue. scRNA-Seq revealed that IFNβ is expressed in immune cell subsets in non-neoplastic human tissues and to a lesser degree in human colon tumor tissues. Forced expression of IFNα13 and IFNβ in colon tumor cells up-regulates major histocompatibility complex I (MHC I) expression and suppresses colon tumor growth in vivo. In human cancer patients, IFNβ expression is positively correlated with human leukocyte antigen (HLA) expression, and IFN-I signaling activation correlates with the patient response to PD-1 blockade immunotherapy. To translate this finding to colon cancer immunotherapy, we formulated a 1,2-dioleoyl-3-trimethylammonium propane (DOTAP)-cholesterol-encapsulated IFNβ-encoding plasmid (IFNBCOL01). IFNBCOL01 transfects colon tumor cells to express IFNβ to increase the level of MHC I expression. IFNBCOL01 therapy transfects tumor cells and tumor-infiltrating immune cells to produce IFNβ to activate MHC I and granzyme B expression and inhibits colon tumor growth in mice. Our data determine that lipid nanoparticle delivery of IFNβ-encoding plasmid DNA enhances tumor immunogenicity and T cell effector function to suppress colon tumor growth in vivo.

Location matters: spatial dynamics of tumor-infiltrating T cell subsets is prognostic in colon cancer.

Colon cancer is a heterogeneous disease and consists of various molecular subtypes. Despite advances in high-throughput expression profiling, limitations remain in predicting clinical outcome and assigning specific treatment to individual cases. Tumor-immune interactions play a critical role, with tumors that activate the immune system having better outcome for the patient. The localization of T cells within tumor epithelium, to enable direct contact, is essential for antitumor function, but bulk DNA/RNA sequencing data lacks spatial distribution information. In this study, we provide spatial T cell tumor distribution and connect these data with previously determined genomic data in the AC-ICAM colon cancer patient cohort. Colon cancer patients (n=90) with transcriptome data available were selected. We used a custom multiplex immunofluorescence assay on colon tumor tissue sections for quantifying T cell subsets spatial distribution in the tumor microenvironment, in terms of cell number, location, mutual distance, and distance to tumor cells. Statistical analyses included the previously determined Immunologic Constant of Rejection (ICR) transcriptome correlation and patient survival, revealing potential prognostic value in T cell spatial distribution. T cell phenotypes were characterized and CD3+CD8-FoxP3- T cells were found to be the predominant tumor-infiltrating subtype while CD3+FoxP3+ T cells and CD3+CD8+ T cells showed similar densities. Spatial distribution analysis elucidated that proliferative T cells, characterized by Ki67 expression, and Granzyme B-expressing T cells were predominantly located within the tumor epithelium. We demonstrated an increase in immune cell density and a decrease in the distance of CD3+CD8+ T cells to the nearest tumor cell, in the immune active, ICR High, immune subtypes. Higher densities of stromal CD3+FoxP3+ T cells showed enhanced survival outcomes, and patients exhibited superior clinical benefits when greater spatial distances were observed between CD3+CD8-FoxP3- or CD3+CD8+ T cells and CD3+FoxP3+ T cells. Our study's in-depth analysis of the spatial distribution and densities of major T cell subtypes within the tumor microenvironment has provided valuable information that paves the way for further research into the intricate relationships between immune cells and colon cancer development.

Vasculogenic mimicry regulates immune infiltration and mutational status of the tumor microenvironment in breast cancer to influence tumor prognosis.

Vasculogenic mimicry (VM) refers to the direct formation of microcirculatory ducts by invasive malignant tumors via cellular phenotypic transformation. However, there is a lack of VM-based biomarkers for breast cancer. We obtained transcriptomic expression data, single cell sequencing data, and clinical data of patients from The Cancer Genome Atlas Program (TCGA) database and GEO database, performed single cell analysis to obtain specific type annotations of breast cancer cells and analyzed their spatial expression analysis. Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene ontology (GO) analyses as well as Gene Set Enrichment Analysis (GSEA) analyses were performed to clarify the biological pathways and tumor functional enrichment relationships of the major expressed genes of VM in the breast cancer bulk data specimens. VM biomarkers were constructed. Meanwhile, the relationship between VM scores and tumor immune infiltration in breast cancer was analyzed using MCPcounter and ssGSEA methods. In addition, we assessed the specific relationship between NDRG1, a key VM gene in breast cancer, and tumor colonization, adhesion and invasion by biological experiments in breast cancer cell lines. The main cell types of breast cancer (BRCA) samples were annotated by single cell transcriptome analysis. Most of the VM-high group was present in epithelial cells, whereas the VM-low group was present in immune and stromal cells. Multiple tumor pathways such as TGFβ p53 and MAPK were closely associated with VM-mediated breast cancer infiltration and invasion. A prognostic model of breast cancer based on VM key genes was constituted. Prognostic stratification of breast cancer was successfully achieved for the TCGA-BRCA and GSE58812 datasets. Through immune infiltration analysis, we found that differential expression of VM markers was associated with multiple immune cell regulation. In MDA-MB-231 and MDA-MB-453 cell lines, we found that the NDRG1 gene significantly promoted colony formation of breast cancer cells. Our constructed VM-related gene-based model of breast cancer biology holds promise for prognostic prediction and patient stratification of breast cancer. This may provide a potentially clinically valuable aid in promoting a deeper understanding of the biological regulation of VM in breast cancer and exploring the specific mechanisms of tumor angiogenesis and breast cancer development.

Comparison of IL-2-antibody to IL-2-Fc with or without stereotactic radiation therapy in CEA immunocompetent mice with CEA positive tumors.

The potent immune effects of interleukin-2 (IL-2) for cancer therapy can be increased by genetic fusion of IL-2 to the Fc domain of an antibody (IL-2-Fc) or tumor targeted by genetic fusion to a whole antibody known as an immunocytokine (ICK). An anti-CEA ICK (M5A-IL-2) was compared to an IL-2-Fc fusion protein using tumor therapy and PET imaging in CEA transgenic immunocompetent mice bearing CEA positive colon or breast tumors. Combination with stereotactic radiation therapy (SRT) was performed with either ICK or IL-2-Fc. ICK and IL-2-Fc had comparable antitumor effects in both tumor models, although ICK had higher tumor uptake and slower blood clearance than an IL-2-Fc. Analysis of IFNγ+ /CD8+ and FoxP3+ /CD4+ T cells revealed higher levels of IFNγ-producing CD8+ T cells in ICK treated mice versus more efficient Treg elimination in IL-2-Fc treated mice. No significant or lasting toxicity was detected for either agent. Combination therapies with SRT revealed comparable efficacy and induction of immune memory for both ICK and IL-2-Fc when mice were rechallenged post-therapy. IL-2-Fc had comparable antitumor efficacy to CEA-targeted M5A-IL-2 ICK, while both fusion proteins induced immune memory when combined with SRT. Differences in the therapeutic mechanisms of both agents were observed.

Immunohistochemical expression of p53, beta-catenin, and PD-L1 in colorectal carcinoma with respect to grade and stage-an observational study in a tertiary care center

Background: Colorectal cancer (CRC) has consistently shown a global rise in incidence. p53 exerts regulatory function in signaling processes, with the p53 mutation accelerating the late stage of colorectal carcinogenesis. Programmed death ligand 1 (PD-L1) is an immune checkpoint regulator whose role in targeted therapy of CRCs needs to be evaluated. Beta-catenin plays a fundamental role in cell adhesion, with long-term effects on disease progression and survival. A detailed evaluation of all these factors is essential to tailoring new therapeutic approaches in advanced-stage cases. Aims and Objectives: To study the immunohistochemical (IHC) expression of p53, PD-L1, and beta-catenin in different histologic grades and stages of colorectal carcinomas. Materials and Methods: A total of 29 cases of segmental colectomy were included in the study population. Tumor sections were sent for IHC study of p53, PD-L1, and beta-catenin and interpreted as per standard protocol. Findings were tabulated against the histologic grade and stages of CRCs. Statistical analysis was done using SPSS 25.0 to test for statistical significance at P<0.05. Results: The study population predominantly consisted of males (66%), mainly in the age group of 46–60 years. p53 was significantly more expressed in left colonic tumors. PD-L1 expression was also significantly associated with histologic grade and nodal metastasis. High beta-catenin expression was seen in well-differentiated adenocarcinomas and lower T and N-stage disease. Positive p53 also correlated with positive PD-L1 expression. However, expression of p53 was also high in tumors with low beta-catenin expression. Conclusion: p53, PD-L1, and beta-catenin may have a role in prognostication and predicting long-term survival outcomes in CRC cases. These may also act as potential therapeutic targets with a more detailed evaluation and a larger sample size of CRC cases.

DNA demethylation and tri-methylation of H3K4 at the TACSTD2 promoter are complementary players for TROP2 regulation in colorectal cancer cells

TROP2 is a powerful cancer driver in colorectal cancer cells. Divergent epigenetic regulation mechanisms for the corresponding TACSTD2 gene exist such as miRNAs or DNA methylation. However, the role of TACSTD2 promoter hypermethylation in colorectal cancer has not been investigated yet. In this study, TROP2 expression strongly correlated with promoter methylation in different colorectal tumor cell lines. Treatment with 5-Azacytidine, a DNMT1 inhibitor, led to demethylation of the TACSTD2 promoter accompanied by an increase in TROP2 protein expression. TROP2 expression correlated with promoter methylation in vivo in human colon tumor tissue, thereby verifying promoter methylation as an important factor in the regulation of TROP2 expression in colorectal cancer. When performing a ChIP-Seq analysis in HCT116 and HT29 cells, we found that TACSTD2 promoter demethylation was accompanied by tri-methylation of H3K4. In silico analysis of GSE156613 data set confirmed that a higher binding of histone mark H3K4me3 around the TACSTD2 promoter was found in TACSTD2 high expressing tumors of colon cancer patients compared to the corresponding adjacent tumor tissue. Moreover, the link between TROP2 and the H3K4me3 code was even evident in tumors showing high intratumoral heterogeneity for TROP2 staining. Our data provide novel evidence for promoter demethylation and simultaneous gains of the active histone mark H3K4me3 across CpG-rich sequences, both being complementary mechanisms in the transcriptional regulation of TACSTD2 in colon cancer. The functional consequences of TROP2 loss in colorectal cancer needs to be further investigated.

Novel mechanism of drug resistance triggered by tumor-associated macrophages through Heat Shock Factor-1 activation

Macrophages constitute a major part of tumor microenvironment, and most of existing data demonstrate their ruling role in the development of anti-drug resistance of cancer cell. One of the most powerful protection system is based on heat shock proteins whose synthesis is triggered by activated Heat Shock Factor-1 (HSF1); the inhibition of the HSF1 with CL-43 sensitized A549 lung cancer cells to the anti-cancer effect of etoposide. Notably, analyzing A549 tumor xenografts in mice we observed nest-like pattern of co-localization of A549 cells demonstrating enhanced expression of HSF1 with macrophages, and decided to check whether the above arrangement has a functional value for both cell types. It was found that the incubation of A549 or DLD1 colon cancer cells with either human monocytes or THP1 monocyte-like cells activated HSF1 and increased resistance to etoposide. Importantly, the same effect was shown when primary cultures of colon tumors were incubated with THP1 cells or with human monocytes. To prove that HSF1 is implicated in enhanced resistance caused by monocytic cells, we generated an A549 cell subline devoid of HSF1 which did not respond to incubation with THP1 cells. The pharmacological inhibition of HSF1 with CL-43 also abolished the effect of THP1 cells on primary tumor cells, highlighting a new target of tumor-associated macrophages in a cell proteostasis mechanism.

Potential prognosis and immunotherapy predictor TFAP2A in pan-cancer.

TFAP2A is critical in regulating the expression of various genes, affecting various biological processes and driving tumorigenesis and tumor development. However, the significance of TFAP2A in carcinogenesis processes remains obscure. In our study, we explored multiple databases including TCGA, GTEx, HPA, cBioPortal, TCIA, and other well-established databases for further analysis to expound TFAP2A expression, genetic alternations, and their relationship with the prognosis and cellular signaling network alternations. GO term and KEGG pathway enrichment analysis as well as GSEA were conducted to examine the common functions of TFAP2A. RT-qPCR, Western Blot and Dual Luciferase Reporter assay were employed to perform experimental validation. TFAP2A mRNA expression level was upregulated and its genetic alternations were frequently present in most cancer types. The enrichment analysis results prompted us to investigate the changes in the tumor immune microenvironment further. We discovered that the expression of TFAP2A was significantly associated with the expression of immune checkpoint genes, immune subtypes, ESTIMATE scores, tumor-infiltrating immune cells, and the possible role of TFAP2A in predicting immunotherapy efficacy. In addition, high TFAP2A expression significantly correlated with several ICP genes, and promoted the expression of PD-L1 on mRNA and protein levels through regulating its expression at the transcriptional level. TFAP2A protein level was upregulated in fresh colon tumor tissue samples compared to that in the adjacent normal tissues, which essentially positively correlated with the expression of PD-L1. Our study suggests that targeting TFAP2A may provide a novel and effective strategy for cancer treatment.

Disease characteristics and prognostic factors of colorectal cancer patients with bone metastasis: A real-world data from Turkey.

Bone metastasis is rarely seen in colorectal cancer (CRC) patients, and there is insufficient data available regarding such cases. The study aimed to identify the prognostic factors and characteristics associated with overall survival in patients with bone metastatic CRC. Data from bone metastatic CRC patients referred to a high-volume tertiary cancer center in Turkey, between January 2018 and April 2021, were retrospectively collected. The records of 150 consecutive patients treated for bone metastases due to CRC were reviewed. Overall survival curves were generated by the Kaplan-Meier method and analyzed using the log-rank test. Median age was 55 years (19-86 years). Bone metastases were more common in men and those with metachronous metastases. The axial skeleton was the most commonly involved site, and patients were frequently presented with single bone metastasis. Peritoneal metastases were significantly correlated with extra-axial metastases (P = 0.002), and radiotherapy was applied to axial metastases significantly, more frequently (P = 0.02). Lung metastasis was also more prevalent in K-RAS mutated patients (P = 0.008). The median survival time from diagnosis of bone metastasis was 8.3 months (95% confidence interval (CI), 5.5-10.6), and the three-year survival rate was 76.9% (95% CI, 69.8-84.0). Multivariate analysis revealed that brain metastases, right-sided colon tumor, high serum ALP, and Ca 19-9 levels were independent poor prognostic factors (P = 0.01, 0.02, <0.001, and 0.04, respectively). The location of CRC correlates significantly with the site of bone metastasis; the prognosis of CRC patients with bone metastasis is very poor, and the significant poor prognostic factors are brain metastases, right-sidedness, high serum ALP, and Ca 19-9 levels. More attention should be paid to bone metastasis in CRC patients.

Unveiling prognosis and traits of dMMR/MSI-H gastric and colorectal cancer after curative surgery: A large-scale, multi-center, retrospective study in China.

729 Background: This study conducted a large-scale multi-center analysis using real-world data from China to comprehensively investigate the clinical characteristics and prognosis of patients with deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H) gastric and colorectal cancer undergoing curative surgery. Additionally, we analyzed postoperative adjuvant treatment effects and recurrence/metastasis patterns. Methods: We retrospectively analyzed 1800 gastric and colorectal cancer patients with dMMR and/or MSI-H confirmed by immunohistochemistry (IHC) and PCR after radical resection from 19 hospitals in China. We compared clinical characteristics among positive patients identified by both testing methods and evaluated their relationship with disease-free survival (DFS) and overall survival (OS). Results: The cohort included 1702 dMMR patients (regardless of MSI status), 667 MSI-H patients (regardless of MMR status), and 46 cases with inconsistent MMR and MSI statuses. No significant differences in overall clinical-pathological characteristics were observed between IHC-dMMR and PCR-MSI-H patients, highlighting the clinical utility of both approaches. Predominantly, MMR protein defects involved MLH1/PMS2 loss (&gt;70%). We found a positive correlation between lymph node metastasis and MLH1/PMS2 protein deficiency (P&lt;0.01) and an inverse correlation trend in cases of MSH2/MSH6 deficiency (P&lt;0.1). Additionally, poorer prognosis was linked to alcohol consumption (DFS, P&lt;0.001), lymph node metastasis (DFS, P&lt;0.001; OS, P&lt;0.001), vascular cancer emboli (OS, P&lt;0.001), and neural invasion (OS, P&lt;0.001). In the dMMR/MSI-H colorectal subgroup, colon cancer patients exhibited superior DFS compared to rectal cancer (P=0.025) and improved DFS with right colon tumors (P=0.01). Patients with MLH2/MSH6 deficiency showed a trend towards better survival, even within the subgroup receiving adjuvant chemotherapy (P=0.067), compared to MLH1/PMS2 and other deficiency disorders. Notably, patients with dMMR and/or MSI-H exhibited a shorter DFS following adjuvant therapy (P&lt;0.001), while OS did not achieve a significant difference, potentially due to the insufficient follow-up duration. Conclusions: This study provides valuable insights into the correlation between MSI-H/dMMR status and clinical characteristics in Chinese patients with gastric and colorectal cancer after radical resection. The findings also illuminate prognostic factors impacting DFS and OS, as well as the intricate relationship between MMR/MSI status and tumor metastasis patterns. It highlights the feasibility of utilizing both MMR-IHC and MSI-PCR for patient selection and enhances our understanding of the clinical management and outcomes of patients with dMMR/MSI-H gastric and colorectal cancer.

Inactivation of pentraxin 3 suppresses M2-like macrophage activity and immunosuppression in colon cancer

BackgroundThe tumor microenvironment is characterized by inflammation-like and immunosuppression situations. Although cancer-associated fibroblasts (CAFs) are among the major stromal cell types in various solid cancers, including colon cancer, the interactions between CAFs and immune cells remains largely uncharacterized. Pentraxin 3 (PTX3) is responsive to proinflammatory cytokines and modulates immunity and tissue remodeling, but its involvement in tumor progression appears to be context-dependent and is unclear.MethodsOpen-access databases were utilized to examine the association of PTX3 expression and the fibroblast signature in colon cancer. Loss-of-function assays, including studies in tamoxifen-induced Ptx3 knockout mice and treatment with an anti-PTX3 neutralizing antibody (WHC-001), were conducted to assess the involvement of PTX3 in colon cancer progression as well as its immunosuppressive effect. Finally, bioinformatic analyses and in vitro assays were performed to reveal the downstream effectors and decipher the involvement of the CREB1/CEBPB axis in response to PTX3 and PTX3-induced promotion of M2 macrophage polarization.ResultsClinically, higher PTX3 expression was positively correlated with fibroblasts and inflammatory response signatures and associated with a poor survival outcome in colon cancer patients. Blockade of PTX3 significantly reduced stromal cell-mediated tumor development. The decrease of the M2 macrophage population and an increase of the cytotoxic CD8+ T-cell population were observed following PTX3 inactivation in allografted colon tumors. We further revealed that activation of cyclic AMP-responsive element-binding protein 1 (CREB1) mediated the PTX3-induced promotion of M2 macrophage polarization.ConclusionsPTX3 contributes to stromal cell-mediated protumor immunity by increasing M2-like macrophage polarization, and inhibition of PTX3 with WHC-001 is a potential therapeutic strategy for colon cancer.

The role of bidirectional communication between the adipokines and the endogenous opioid system in an experimental mouse model of colitis-associated colorectal cancer.

Colorectal cancer (CRC) is one of the leading causes of death globally. Multiple factors may contribute to the pathogenesis of CRC, including the abnormalities in the functioning of the endogenous opioid system (EOS) or adiponectin-related signaling. The aim of our study was to evaluate if differences in the expression of opioid receptors (ORs) influence the development of CRC and if modulation of adiponectin receptors using AdipoRon, a selective AdipoR1 receptor agonist, affects colorectal carcinogenesis. Naltrexone, an opioid receptor antagonist, was injected intraperitoneally every second day for 2weeks, at the dose of 1mg/kg in healthy Balb/C mice to induce changes in ORs expression. CRC was induced by a single intraperitoneal injection of azoxymethane (AOM) and the addition of dextran sodium sulfate (DSS) into drinking water in three-week cycles. The development of CRC was assessed using macro- and microscopic scoring and molecular analysis (RT qPCR, ELISA)after 14 weeks. Naltrexone significantly increased the mRNA expression of Oprm1, Oprd1, and Oprk1 in the mouse colon and in the brain (non-significantly). The pretreatment of mice with naltrexone aggravated the course of CRC (as indicated by tumor area, colon thickness, and spleen weight). The level of circulatory adiponectin was lowered in mice with CRC and increased in the colon as compared with healthy mice. The β-endorphin level was increased in the plasma of mice with CRC and decreased in the colon as compared to healthy mice. AdipoRon, AdipoR1 agonist, worsened the CRC development, and pretreatment with naltrexone enhanced this negative effect in mice. CRC did not affect the expression of the Adipor1 gene, but the Adipor1 level was increased in mice pretreated with naltrexone (AOM/DSS and healthy mice). AdipoRon did not influence the expression of opioid receptors at the mRNA level in the colon of mice with CRC. The mRNA expression of Ptgs2, Il6, Nos2, Il1b, Il18, Gsdmd, and Rela was increased in mice with CRC as compared to the healthy colon. AdipoRon significantly decreased mRNA expression of Ptgs2, Il6, Il1b, and Il18 as compared to CRC mice. EOS and adiponectin-related signaling may play a role in the pathogenesis of CRC and these systems may present some additivity during carcinogenesis.

Linking cell mechanical memory and cancer metastasis.

Metastasis causes most cancer-related deaths; however, the efficacy of anti-metastatic drugs is limited by incomplete understanding of the biological mechanisms that drive metastasis. Focusing on the mechanics of metastasis, we propose that the ability of tumour cells to survive the metastatic process is enhanced by mechanical stresses in the primary tumour microenvironment that select for well-adapted cells. In this Perspective, we suggest that biophysical adaptations favourable for metastasis are retained via mechanical memory, such that the extent of memory is influenced by both the magnitude and duration of the mechanical stress. Among the mechanical cues present in the primary tumour microenvironment, we focus on high matrix stiffness to illustrate how it alters tumour cell proliferation, survival, secretion of molecular factors, force generation, deformability, migration and invasion. We particularly centre our discussion on potential mechanisms of mechanical memory formation and retention via mechanotransduction and persistent epigenetic changes. Indeed, we propose that the biophysical adaptations that are induced by this process are retained throughout the metastatic process to improve tumour cell extravasation, survival and colonization in the distant organ. Deciphering mechanical memory mechanisms will be key to discovering a new class of anti-metastatic drugs.

Matrix metalloproteinases as biomarkers and therapeutic targets in colitis-associated cancer.

Colorectal cancer (CRC) remains a major cause of morbidity and mortality. Therapeutic approaches for advanced CRC are limited and rarely provide long-term benefit. Enzymes comprising the 24-member matrix metalloproteinase (MMP) family of zinc- and calcium-dependent endopeptidases are key players in extracellular matrix degradation, a requirement for colon tumor expansion, invasion, and metastasis; hence, MMPs are an important research focus. Compared to sporadic CRC, less is known regarding the molecular mechanisms and the role of MMPs in the development and progression of colitis-associated cancer (CAC) - CRC on a background of chronic inflammatory bowel disease (IBD) - primarily ulcerative colitis and Crohn's disease. Hence, the potential of MMPs as biomarkers and therapeutic targets for CAC is uncertain. Our goal was to review data regarding the role of MMPs in the development and progression of CAC. We sought to identify promising prognostic and therapeutic opportunities and novel lines of investigation. A key observation is that since MMPs may be more active in early phases of CAC, using MMPs as biomarkers of advancing neoplasia and as potential therapeutic targets for adjuvant therapy in those with advanced stage primary CAC rather than overt metastases may yield more favorable outcomes.

Evaluation of Factors That Contribute to Intraoperative and Postoperative Complications Following Colorectal Cancer Surgeries at King Abdulaziz University Hospital, Jeddah, Saudi Arabia.

Colorectal cancer (CRC) is a major contributor to cancer-related mortality and morbidity due to its high prevalence. Surgery remains the curative option. Colorectal cancer patients come to our institute at an advanced stage due to the lack of adequate national screening programs in developing countries. This carries a particularly high risk of morbidity and mortality. In this study, we aim to provide an overview of the complications of colorectal cancer surgery and to describe the preoperative and intraoperative factors associated with it. This retrospective record review was done at King Abdulaziz University Hospital (KAUH), a tertiary center in Jeddah, Saudi Arabia. It included all patients aged 18 and older who have undergone colorectal cancer surgeries from January 2017 until August 2022. In our sample of 195 patients, 52.3% of the patients were males. The mean age of our sample was 59.32 ± 13.21. We found that 19 (9.7%) patients had an intraoperative complication (IOC). The most frequent IOC was bleeding reported in seven patients (3.6%), followed by intestinal injury in three (1.2%), bladder injury in three (1.2%), and ureter injury in three (1.2%). Regarding preoperative lab tests, patients who had low blood albumin levels (P = 0.004) and high preoperative white blood cell count (WBC; P = 0.015) were more likely to experience IOC. There was a statistically significant relationship between the patient's ASA score and IOC (P = 0.011).Postoperative complications (POC) occurred in 58 patients (29.7%). The most frequent POC was surgical site infection (SSI; 16.4%), followed by urinary tract infections (UTI) (6.7%) and prolonged postoperative ileus (5.6%). Patients who initially presented with vomiting (P = 0.015), had free air on a preoperative abdominal computed tomography (CT) scan (P = 0.028), required intraoperative blood transfusions (P = 0.033), were diagnosed with transverse colon tumors (P = 0.045), and required longer hospital stays (P = 0.011) were found to have a higher rate of POC. The incidence of colorectal cancer is increasing, and surgery is a successful treatment option. However, complications from surgery may result in morbidities and prolonged hospital stays. The risk of IOC is increased by preoperative variables such as high WBC levels, low albumin, and ASA scores. Patients with initial obstruction signs, free air on CT scans, intraoperative blood transfusions, transverse colon tumors, and longer hospital stays have a higher rate of POC. Patient monitoring and the provision of standardized clinical tools enhance general survival and quality of life.

Preoperative 18F-FDG PET/CT in Patients with Presumed Localized Colon Cancer: A Prospective Study with Long-Term Follow-Up.

We analyzed whether preoperative 18F-FDG PET/CT adds to conventional primary staging in patients with presumed non-metastatic colonic cancer (CC). The prognostic role of 18F-FDG uptake in the primary tumor was evaluated after a mean follow-up of 15 years. Patients with a new diagnosis of presumed localized CC were prospectively enrolled and underwent presurgical 18F-FDG PET/CT. For each colon lesion, SUVmax, SUVpeak, TLG, and MTV were assessed and tested as prognostic factors. Forty-eight patients were included. Post-surgery pathology identified a total of 103 colon lesions, including 58 invasive adenocarcinomas, 4 in situ adenocarcinomas, 3 adenomas with high-grade dysplasia, and 38 adenomas with low-grade dysplasia. Per lesion sensitivity, specificity, positive (PPVs) and negative predictive values (NPVs) for colonic primary tumor detection were 78%, 97%, 98%, and 73% for conventional workup, and 94%, 87%, 92%, and 89% for 18F-FDG PET/CT. Only sensitivity was significantly different between 18F-FDG PET/CT and conventional workup. PET detected an additional ten pathological colonic lesions in seven patients. SUVmax, SUVpeak, and TLG showed significant differences between invasive adenocarcinomas, in situ adenocarcinomas, and high-grade dysplasia compared to low-grade dysplasia. There was a statistically significant difference between pT1-pT2 and pT3-pT4 adenocarcinomas. On patient-based analysis, sensitivity, specificity, PPV, and NPV for nodal staging were 22%, 84%, 44%, and 65% for CECT, and 33%, 90%, 67%, and 70% for 18F-FDG PET/CT, without a statistically significant difference. PET/CT also identified unknown metastatic spread and one synchronous lung cancer in four patients. Overall, 18F-FDG PETCT had an additional diagnostic value in 11 out of 48 patients (23%). 18F-FDG uptake of the primary tumor did not predict nodal or distant metastases. The difference in disease-free survival categorized by median SUVmax, SUVpeak, TLG, and MTV was not significant. Finally, preoperative 18F-FDG PET/CT is valuable in detecting potential colon lesions not visualized by conventional workups, especially in cases of incomplete colonoscopy. It effectively highlights distant metastases but exhibits limitations for N staging. Mainly due to the relatively small sample size, the quantitative analysis of 18F-FDG uptake in the primary tumor did not reveal any association with recurrence or disease-free survival, adding no significant prognostic information.

Achieving precise non-invasive ROS spatiotemporal manipulation for colon cancer immunotherapy

Colon cancer (CC) stands as a formidable global health challenge, ranking as the third leading cause of cancer-related mortality. Traditional photodynamic therapy encounters limitations stemming from the limited penetration depth of light and the effective regulation of reactive oxygen species (ROS). Here, we present an in-situ ROS spatiotemporal manipulation system that synergizes the power of piezoelectric nanoparticles with potent immune adjuvants. This exclusive ROS nanogenerator exhibits precision in targeting colon tumor sites, inducing controlled oxidative stress to eliminate malignant cells, while simultaneously unleashing the full potential of the immune system to suppress cancer cell growth and impede metastasis. Notably, this system achieves spatiotemporal manipulation of ROS through piezocatalytic mechanisms triggered self-generated ROS. Moreover, it skillfully customizes ROS production in response to tumor size, optimizing therapeutic efficacy with precision. To enhance the therapeutic efficacy, glucan, a bioactive polysaccharide that augments the immune response while simultaneously inhibiting the spread of cancer cells, is integrated. This cancer treatment approach is enabling precise ROS generation and immune modulation at the tumor site, ushering in a new era of dynamic immunotherapy.