International Journal of Molecular Sciences

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14 pages, 3317 KiB

Open AccessArticle

Proinflammatory Microenvironment in Adenocarcinoma Tissue of Colorectal Carcinoma

by Slobodan Todorović, Miljan S. Ćeranić, Borislav Tošković, Miloš Diklić, Olivera Mitrović Ajtić, Tijana Subotički, Milica Vukotić, Teodora Dragojević, Emilija Živković, Svetlana Oprić, Miodrag Stojiljkovic, Jasna Gačić, Nataša Čolaković, Bogdan Crnokrak, Vladan P. Čokić and Dragoslava Đikić

Int. J. Mol. Sci. 2024, 25(18), 10062; https://doi.org/10.3390/ijms251810062 - 19 Sep 2024

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Abstract

Cancer-promoting proinflammatory microenvironment influences colorectal cancer (CRC) development. We examined the biomarkers of inflammation, intestinal differentiation, and DNA activity correlated with the clinical parameters to observe progression and prognosis in the adenocarcinoma subtype of CRC. Their immunohistology, immunoblotting, and RT-PCR analyses were performed [...] Read more.

Cancer-promoting proinflammatory microenvironment influences colorectal cancer (CRC) development. We examined the biomarkers of inflammation, intestinal differentiation, and DNA activity correlated with the clinical parameters to observe progression and prognosis in the adenocarcinoma subtype of CRC. Their immunohistology, immunoblotting, and RT-PCR analyses were performed in the adenocarcinoma and neighboring healthy tissues of 64 patients with CRC after routine colorectal surgery. Proinflammatory nuclear factor kappa B (NFκB) signaling as well as interleukin 6 (IL-6) and S100 protein levels were upregulated in adenocarcinoma compared with nearby healthy colon tissue. In contrast to nitrotyrosine expression, the oxidative stress marker 8-Hydroxy-2′-deoxyguanosine (8-OHdG) was increased in adenocarcinoma tissue. Biomarkers of intestinal differentiation β-catenin and mucin 2 (MUC2) were inversely regulated, with the former upregulated in adenocarcinoma tissue and positively correlated with tumor marker CA19-9. Downregulation of MUC2 expression correlated with the increased 2-year survival rate of patients with CRC. Proliferation-related mammalian target of rapamycin (mTOR) signaling was activated, and Ki67 frequency was three-fold augmented in positive correlation with metastasis and cancer stage, respectively. Conclusion: We demonstrated a parallel induction of oxidative stress and inflammation biomarkers in adenocarcinoma tissue that was not reflected in the neighboring healthy colon tissue of CRC. The expansiveness of colorectal adenocarcinoma was confirmed by irregular intestinal differentiation and elevated proliferation biomarkers, predominantly Ki67. The origin of the linked inflammatory factors was in adenocarcinoma tissue, with an accompanying systemic immune response. Full article

(This article belongs to the Special Issue Systemic and Mucosal Inflammation in Colorectal Cancer: Underlying Factors, Significance, and Related Biomarkers)

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15 pages, 3236 KiB

Open AccessArticle

Berberine Improves Cancer-Derived Myocardial Impairment in Experimental Cachexia Models by Targeting High-Mobility Group Box-1

by Kei Goto, Rina Fujiwara-Tani, Shota Nukaga, Yoshihiro Miyagawa, Isao Kawahara, Ryoichi Nishida, Ayaka Ikemoto, Rika Sasaki, Ruiko Ogata, Shingo Kishi, Yi Luo, Kiyomu Fujii, Hitoshi Ohmori and Hiroki Kuniyasu

Int. J. Mol. Sci. 2024, 25(9), 4735; https://doi.org/10.3390/ijms25094735 - 26 Apr 2024

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Abstract

Cardiac disorders in cancer patients pose significant challenges to disease prognosis. While it has been established that these disorders are linked to cancer cells, the precise underlying mechanisms remain elusive. In this study, we investigated the impact of cancerous ascites from the rat [...] Read more.

Cardiac disorders in cancer patients pose significant challenges to disease prognosis. While it has been established that these disorders are linked to cancer cells, the precise underlying mechanisms remain elusive. In this study, we investigated the impact of cancerous ascites from the rat colonic carcinoma cell line RCN9 on H9c2 cardiomyoblast cells. We found that the ascites reduced mitochondrial volume, increased oxidative stress, and decreased membrane potential in the cardiomyoblast cells, leading to apoptosis and autophagy. Although the ascites fluid contained a substantial amount of high-mobility group box-1 (HMGB1), we observed that neutralizing HMGB1 with a specific antibody mitigated the damage inflicted on myocardial cells. Our mechanistic investigations revealed that HMGB1 activated both nuclear factor κB and phosphoinositide 3-kinases-AKT signals through HMGB1 receptors, namely the receptor for advanced glycation end products and toll-like receptor-4, thereby promoting apoptosis and autophagy. In contrast, treatment with berberine (BBR) induced the expression of miR-181c-5p and miR-340-5p while suppressing HMGB1 expression in RCN9 cells. Furthermore, BBR reduced HMGB1 receptor expression in cardiomyocytes, consequently mitigating HMGB1-induced damage. We validated the myocardial protective effects of BBR in a cachectic rat model. These findings underscore the strong association between HMGB1 and cancer cachexia, highlighting BBR as a promising therapeutic agent for myocardial protection through HMGB1 suppression and modulation of the signaling system. Full article

(This article belongs to the Special Issue Systemic and Mucosal Inflammation in Colorectal Cancer: Underlying Factors, Significance, and Related Biomarkers)

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20 pages, 5411 KiB

Open AccessArticle

Cellular Responses to Extracellular Vesicles as Potential Markers of Colorectal Cancer Progression

by Sonia Guarnerio, Robert Tempest, Rawan Maani, Stuart Hunt, Laura M. Cole, Christine L. Le Maitre, Keith Chapple and Nicholas Peake

Int. J. Mol. Sci. 2023, 24(23), 16755; https://doi.org/10.3390/ijms242316755 - 25 Nov 2023

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Abstract

The development of novel screening tests aims to support early asymptomatic diagnosis and subtyping patients according to similar traits in the heterogeneous cancer cohort. Extracellular vesicles (EVs) are promising candidates for the detection of disease markers from bodily fluids, but limitations in the [...] Read more.

The development of novel screening tests aims to support early asymptomatic diagnosis and subtyping patients according to similar traits in the heterogeneous cancer cohort. Extracellular vesicles (EVs) are promising candidates for the detection of disease markers from bodily fluids, but limitations in the standardisation of isolation methods and the intrinsic EV heterogeneity obtained from liquid biopsies are currently obstacles to clinical adoption. Here, cellular responses to cancer EVs were initially explored as potential complementary biomarkers for stage separation using colorectal cancer (CRC) SW480 and SW620 cell line models. A pilot study on a small cohort of CRC patients and controls was then developed by performing a multivariate analysis of cellular responses to plasma-derived EVs. Several cell activities and markers involved in tumour microenvironment pathways were influenced by the treatment of cell line EVs in a stage-dependent manner. The multivariate analysis combining plasma EV markers and cellular responses to plasma EVs was able to separate patients according to disease stage. This preliminary study offers the potential of considering cellular responses to EVs in combination with EV biomarkers in the development of screening methods. Full article

(This article belongs to the Special Issue Systemic and Mucosal Inflammation in Colorectal Cancer: Underlying Factors, Significance, and Related Biomarkers)

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14 pages, 2063 KiB

Open AccessArticle

Immunometabolic Profile Associated with Progressive Damage of the Intestinal Mucosa in Adults Screened for Colorectal Cancer: Association with Diet

by Celestino González, Sergio Ruiz-Saavedra, María Gómez-Martín, Aida Zapico, Patricia López-Suarez, Ana Suárez, Adolfo Suárez González, Carmen González del Rey, Elena Díaz, Ana Alonso, Clara G. de los Reyes-Gavilán and Sonia González

Int. J. Mol. Sci. 2023, 24(22), 16451; https://doi.org/10.3390/ijms242216451 - 17 Nov 2023

Cited by 1 | Viewed by 2029

Abstract

Environmental factors such as diet and lifestyle have been shown to influence the development of some intestinal mucosal lesions that may be precursors of colorectal cancer (CRC). The presence of these alterations seems to be associated with misbalanced immunological parameter levels. However, it [...] Read more.

Environmental factors such as diet and lifestyle have been shown to influence the development of some intestinal mucosal lesions that may be precursors of colorectal cancer (CRC). The presence of these alterations seems to be associated with misbalanced immunological parameter levels. However, it is still unclear as to which immunological parameters are altered in each phase of CRC development. In this work, we aimed to study the potential relationships of immunological and metabolic parameters with diet in a CRC-related lesion context. Dietary information was obtained using an annual semi-quantitative food-frequency questionnaire (FFQ) from 93 volunteers classified via colonoscopy examination according to the presence of intestinal polyps or adenocarcinoma. Cytokines, chemokines, and adipokines were determined from serum samples. We observed a reduction in adiponectin according to the damage to the mucosa, accompanied by an increase and decrease in C-X-C motif chemokine ligand 10 (CXCL10) and resistin, respectively, in CRC cases. The presence of aberrant crypt foci (ACF) in the polyp group was associated with higher tumor necrosis factor-alpha (TNF-α) concentrations. Vegetables were directly correlated with adiponectin and resistin levels, while the opposite occurred with red meat. A bioactive compound, soluble pectin, showed a negative association with TNF-α. Future dietary strategies could be developed to modulate specific immunological parameters in the context of CRC. Full article

(This article belongs to the Special Issue Systemic and Mucosal Inflammation in Colorectal Cancer: Underlying Factors, Significance, and Related Biomarkers)

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13 pages, 3435 KiB

Open AccessArticle

HP1γ Prevents Activation of the cGAS/STING Pathway by Preserving Nuclear Envelope and Genomic Integrity in Colon Adenocarcinoma Cells

by Jorge Mata-Garrido, Laura Frizzi, Thien Nguyen, Xiangyan He, Yunhua Chang-Marchand, Yao Xiang, Caroline Reisacher, Iñigo Casafont and Laurence Arbibe

Int. J. Mol. Sci. 2023, 24(8), 7347; https://doi.org/10.3390/ijms24087347 - 16 Apr 2023

Cited by 2 | Viewed by 1971

Abstract

Chronic inflammatory processes in the intestine result in serious conditions such as inflammatory bowel disease (IBD) and cancer. An increased detection of cytoplasmic DNA sensors has been reported in the IBD colon mucosa, suggesting their contribution in mucosal inflammation. Yet, the mechanisms altering [...] Read more.

Chronic inflammatory processes in the intestine result in serious conditions such as inflammatory bowel disease (IBD) and cancer. An increased detection of cytoplasmic DNA sensors has been reported in the IBD colon mucosa, suggesting their contribution in mucosal inflammation. Yet, the mechanisms altering DNA homeostasis and triggering the activation of DNA sensors remain poorly understood. In this study, we show that the epigenetic regulator HP1γ plays a role in preserving nuclear envelope and genomic integrity in enterocytic cells, thereby protecting against the presence of cytoplasmic DNA. Accordingly, HP1 loss of function led to the increased detection of cGAS/STING, a cytoplasmic DNA sensor that triggers inflammation. Thus, in addition to its role as a transcriptional silencer, HP1γ may also exert anti-inflammatory properties by preventing the activation of the endogenous cytoplasmic DNA response in the gut epithelium. Full article

(This article belongs to the Special Issue Systemic and Mucosal Inflammation in Colorectal Cancer: Underlying Factors, Significance, and Related Biomarkers)

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Review

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18 pages, 3076 KiB

Open AccessReview

Inflammation and Colorectal Cancer: A Meta-Analysis of the Prognostic Significance of the Systemic Immune–Inflammation Index (SII) and the Systemic Inflammation Response Index (SIRI)

by Otilia Menyhart, János Tibor Fekete and Balázs Győrffy

Int. J. Mol. Sci. 2024, 25(15), 8441; https://doi.org/10.3390/ijms25158441 - 2 Aug 2024

Viewed by 1048

Abstract

The overall prognosis for colorectal cancer (CRC) remains challenging as the survival time varies widely, even in patients with the same stage of disease. Recent studies suggest prognostic relevance of the novel markers of systemic inflammation, the systemic immune–inflammation index (SII), and the [...] Read more.

The overall prognosis for colorectal cancer (CRC) remains challenging as the survival time varies widely, even in patients with the same stage of disease. Recent studies suggest prognostic relevance of the novel markers of systemic inflammation, the systemic immune–inflammation index (SII), and the systemic inflammation response index (SIRI). We conducted a comprehensive meta-analysis to assess the prognostic significance of the SII and the SIRI in CRC. We searched the relevant literature for observational studies, and random effects models were employed to conduct a statistical analysis using the metaanalysisonline.com platform. Pooled effect sizes were reported with hazard ratios (HRs) and corresponding 95% confidence intervals (CI). Data from 29 studies published between 2016 and 2024, comprising 10,091 participants, were included in our meta-analysis on SII. CRC patients with high SII levels had worse disease outcomes, which were associated with poor OS (HR: 1.75; 95% CI: 1.4–2.19) and poor PFS/DFS/RFS (HR: 1.25; 95% CI: 1.18–1.33). This increased risk of worse OS was present irrespective of the treatment strategy, sample size (<220 and ≥220), and cutoff used to define high and low SII (<550 and ≥550) groups. Based on data from five studies comprising 2362 participants, we found a strong association between the high SIRI and worse OS (HR: 2.65; 95% CI: 1.6–4.38) and DFS/RFS (HR: 2.04; 95% CI: 1.42–2.93). According to our results, both the SII and SIRI hold great promise as prognostic markers in CRC. Further validations are needed for their age- and stage-specific utility in the clinical routine. Full article

(This article belongs to the Special Issue Systemic and Mucosal Inflammation in Colorectal Cancer: Underlying Factors, Significance, and Related Biomarkers)

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21 pages, 1206 KiB

Open AccessReview

The Crucial Role of Inflammation and the Immune System in Colorectal Cancer Carcinogenesis: A Comprehensive Perspective

by Antonio Manuel Burgos-Molina, Teresa Téllez Santana, Maximino Redondo and María José Bravo Romero

Int. J. Mol. Sci. 2024, 25(11), 6188; https://doi.org/10.3390/ijms25116188 - 4 Jun 2024

Cited by 2 | Viewed by 2764

Abstract

Chronic inflammation drives the growth of colorectal cancer through the dysregulation of molecular pathways within the immune system. Infiltration of immune cells, such as macrophages, into tumoral regions results in the release of proinflammatory cytokines (IL-6; IL-17; TNF-α), fostering tumor proliferation, survival, and [...] Read more.

Chronic inflammation drives the growth of colorectal cancer through the dysregulation of molecular pathways within the immune system. Infiltration of immune cells, such as macrophages, into tumoral regions results in the release of proinflammatory cytokines (IL-6; IL-17; TNF-α), fostering tumor proliferation, survival, and invasion. Tumors employ various mechanisms to evade immune surveillance, effectively ‘cloaking’ themselves from detection and subsequent attack. A comprehensive understanding of these intricate molecular interactions is paramount for advancing novel strategies aimed at modulating the immune response against cancer. Full article

(This article belongs to the Special Issue Systemic and Mucosal Inflammation in Colorectal Cancer: Underlying Factors, Significance, and Related Biomarkers)

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20 pages, 3307 KiB

Open AccessReview

Different Roles of Apoptosis and Autophagy in the Development of Human Colorectal Cancer

by Giulia Orlandi, Luca Roncucci, Gianluca Carnevale and Paola Sena

Int. J. Mol. Sci. 2023, 24(12), 10201; https://doi.org/10.3390/ijms241210201 - 15 Jun 2023

Cited by 10 | Viewed by 2512

Abstract

Colorectal cancer (CRC) remains a major life-threatening malignancy, despite numerous therapeutic and screening attempts. Apoptosis and autophagy are two processes that share common signaling pathways, are linked by functional relationships and have similar protein components. During the development of cancer, the two processes [...] Read more.

Colorectal cancer (CRC) remains a major life-threatening malignancy, despite numerous therapeutic and screening attempts. Apoptosis and autophagy are two processes that share common signaling pathways, are linked by functional relationships and have similar protein components. During the development of cancer, the two processes can trigger simultaneously in the same cell, causing, in some cases, an inhibition of autophagy by apoptosis or apoptosis by autophagy. Malignant cells that have accumulated genetic alterations can take advantage of any alterations in the apoptotic process and as a result, progress easily in the cancerous transformation. Autophagy often plays a suppressive role during the initial stages of carcinogenicity, while in the later stages of cancer development it can play a promoting role. It is extremely important to determine the regulation of this duality of autophagy in the development of CRC and to identify the molecules involved, as well as the signals and the mechanisms behind it. All the reported experimental results indicate that, while the antagonistic effects of autophagy and apoptosis occur in an adverse environment characterized by deprivation of oxygen and nutrients, leading to the formation and development of CRC, the effects of promotion and collaboration usually involve an auxiliary role of autophagy compared to apoptosis. In this review, we elucidate the different roles of autophagy and apoptosis in human CRC development. Full article

(This article belongs to the Special Issue Systemic and Mucosal Inflammation in Colorectal Cancer: Underlying Factors, Significance, and Related Biomarkers)

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