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Ga-FAPI-04 Positron Emission Tomography Distinguishes Malignancy From F-FDG-Avid Colorectal Lesions.International Journal of Radiation... Jan 2024Lesions with a high uptake of F-fluorodeoxyglucose (F-FDG) on positron emission tomography-computed tomography (PET-CT) can be benign and malignant. New radiotracers,...
PURPOSE
Lesions with a high uptake of F-fluorodeoxyglucose (F-FDG) on positron emission tomography-computed tomography (PET-CT) can be benign and malignant. New radiotracers, such as the gallium 68 (Ga)-labeled fibroblast activation protein inhibitor 4 (FAPI-04), could be used to diagnose colorectal carcinoma. This study aimed to evaluate the efficacy of Ga-FAPI-04 PET in differentiating benign from malignant F-FDG-avid colorectal lesions.
METHODS AND MATERIALS
An azoxymethane/dextran sodium sulfate (AOM/DSS)-induced rat colorectal tumor model was developed. Double-tracer Ga-FAPI-04 and F-FDG PET-CT were applied in the rat model and 22 patients. The PET-CT data were analyzed with enteroscopy, histopathologic observations, immunohistochemistry (IHC) staining, and radioautography results. One hundred seventy-two patients with pathologically confirmed colorectal lesions were enrolled in FAP IHC staining.
RESULTS
We found that Ga-FAPI-04 PET-CT imaging accurately distinguished the malignant from benign inflammatory lesions in an AOM/DSS-induced rat colorectal tumor model. Of 22 patients with gastric cancer but without colorectal carcinoma, 8 had F-FDG uptake in the colorectum, but Ga-FAPI-04 PET was negative in these sites. An inflammatory lesion or adenoma did not interfere with Ga-FAPI-04 PET imaging. Among the F-FDG-avid colorectal lesions, 80 of 94 pathologically malignant lesions (85.1%) were FAP-positive, and only 16 of the 78 premalignant or benign lesions (20.5%) had a weak Ga-FAPI-04 uptake.
CONCLUSIONS
Ga-FAPI-04 PET-CT could be used to distinguish between benign and malignant F-FDG-avid colorectal lesions.
Topics: Humans; Animals; Rats; Fluorodeoxyglucose F18; Positron Emission Tomography Computed Tomography; Gallium Radioisotopes; Positron-Emission Tomography; Quinolines; Colorectal Neoplasms; Azoxymethane
PubMed: 37634891
DOI: 10.1016/j.ijrobp.2023.08.019 -
Journal of Gastrointestinal Oncology Dec 2023Chronic or recurrent inflammatory injury to the intestinal mucosa is closely related to inflammation-related colorectal cancer (CRC). This study aimed to examine the...
BACKGROUND
Chronic or recurrent inflammatory injury to the intestinal mucosa is closely related to inflammation-related colorectal cancer (CRC). This study aimed to examine the protective effects of palbociclib, a stimulator of interferon genes (STING) antagonist, on colitis-related colorectal carcinogenesis.
METHODS
Bioinformatic analyses, including Gene Ontology (GO) enrichment, gene set enrichment analysis (GSEA), and network analysis, were conducted. Male C57BL/6 mice were administered azoxymethane (AOM) and dextran sulfate sodium (DSS), followed by treatment with palbociclib for 6 weeks. The general conditions of mice were observed and recorded. The colon histopathology was assessed based on hematoxylin and eosin (H&E) staining results. Relative messenger RNA (mRNA) expression levels of interferon b1 (), interleukin 6 (), and interleukin 1b ( in colon were estimated based on quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) analysis.
RESULTS
The STING signaling pathway was significantly upregulated in stages III and IV of CRC in The Cancer Genome Atlas (TCGA)-CRC cohort. After treatment with AOM/DSS, the weight of mice decreased significantly, whereas administration of palbociclib partially reversed this trend. The mouse colon treated with AOM/DSS showed significant pathological damages, disorderly epithelial cell structure, atypical hyperplasia, and infiltration of several inflammatory cell types; however, the colon damage was remarkably reduced upon treatment with palbociclib. It was also found that palbociclib almost abolished the increase in the downstream effectors of STING-mediated transcription in the colon tissue treated with AOM/DSS, as evidenced by the transcription levels of , , and
CONCLUSIONS
These findings indicate that the STING pathway is closely associated with CRC. Palbociclib significantly alleviates tumor development in AOM/DSS-induced colitis-associated CRC.
PubMed: 38196536
DOI: 10.21037/jgo-23-860 -
Molecular Oncology Nov 2023The incidence of colitis-associated colorectal cancer (CAC) has increased due to a high-nutrient diet, increased environmental stimuli and inherited gene mutations. To...
The incidence of colitis-associated colorectal cancer (CAC) has increased due to a high-nutrient diet, increased environmental stimuli and inherited gene mutations. To adequately treat CAC, drugs should be developed by identifying novel therapeutic targets. E3 ubiquitin-protein ligase pellino homolog 3 (pellino 3; Peli3) is a RING-type E3 ubiquitin ligase involved in inflammatory signalling; however, its role in the development and progression of CAC has not been elucidated. In this study, we studied Peli3-deficient mice in an azoxymethane/dextran sulphate sodium-induced CAC model. We observed that Peli3 promotes colorectal carcinogenesis with increased tumour burden and oncogenic signalling pathways. Ablation of Peli3 reduced inflammatory signalling activation at the early stage of carcinogenesis. Mechanistic studies indicate that Peli3 enhances toll-like receptor 4 (TLR4)-mediated inflammation through ubiquitination-dependent degradation of interferon regulatory factor 4, a negative regulator of TLR4 in macrophages. Our study suggests an important molecular link between Peli3 and colonic inflammation-mediated carcinogenesis. Furthermore, Peli3 can be a therapeutic target in the prevention and treatment of CAC.
Topics: Animals; Mice; Carcinogenesis; Colitis-Associated Neoplasms; Inflammation; Interferon Regulatory Factors; Mice, Inbred C57BL; Toll-Like Receptor 4; Ubiquitin-Protein Ligases
PubMed: 37341064
DOI: 10.1002/1878-0261.13475 -
Cardiovascular Research May 2024Heart failure (HF) and cancer are the leading causes of death worldwide. Epidemiological studies revealed that HF patients are prone to develop cancer. Preclinical...
AIMS
Heart failure (HF) and cancer are the leading causes of death worldwide. Epidemiological studies revealed that HF patients are prone to develop cancer. Preclinical studies provided some insights into this connection, but the exact mechanisms remain elusive. In colorectal cancer (CRC), gut microbial dysbiosis is linked to cancer progression and recent studies have shown that HF patients display microbial dysbiosis. This current study focussed on the effects of HF-induced microbial dysbiosis on colonic tumour formation.
METHODS AND RESULTS
C57BL/6J mice were subjected to myocardial infarction (MI), with sham surgery as control. After six weeks faeces were collected, processed for 16 s rRNA sequencing, and pooled for faecal microbiota transplantation. CRC tumour growth was provoked in germ-free mice by treating them with Azoxymethane/Dextran sodium sulphate. The CRC mice were transplanted with faeces from MI or sham mice. MI-induced HF resulted in microbial dysbiosis, characterized by a decreased α-diversity and microbial alterations on the genus level, several of which have been associated with CRC. We then performed faecal microbiota transplantation with faeces from HF mice in CRC mice, which resulted in a higher endoscopic disease score and an increase in the number of tumours in CRC mice.
CONCLUSION
We demonstrated that MI-induced HF contributes to colonic tumour formation by altering the gut microbiota composition, providing a mechanistic explanation for the observed association between HF and increased risk for cancer. Targeting the microbiome may present as a tool to mitigate HF-associated co-morbidities, especially cancer.
Topics: Animals; Dysbiosis; Mice, Inbred C57BL; Gastrointestinal Microbiome; Fecal Microbiota Transplantation; Disease Models, Animal; Myocardial Infarction; Heart Failure; Male; Colon; Ribotyping; Colonic Neoplasms; Bacteria; Feces; Host-Pathogen Interactions
PubMed: 38400709
DOI: 10.1093/cvr/cvae038 -
BMC Cancer Aug 2023It is widely accepted that chronic inflammatory bowel diseases significantly higher a risk for colorectal cancer development. Among different types of treatments for...
BACKGROUND
It is widely accepted that chronic inflammatory bowel diseases significantly higher a risk for colorectal cancer development. Among different types of treatments for patients with colon cancer, novel protein-based therapeutic strategies are considered.
AIM
To explore the effect of human plasma alpha-1 antitrypsin (AAT) protein in the chemically induced mouse model of colorectal cancer.
METHODS
BALB/c mice with azoxymethane/dextran sodium sulfate (AOM/DSS)-induced colitis-associated colorectal cancer (CAC), we intraperitoneally treated with commercial preparation of human plasma AAT (4 mg per mouse). Effects of this therapy were evaluated histologically, and by immunohistochemical and gene expression assays.
RESULTS
When compared with non-treated controls, AOM/DSS mice receiving AAT therapy exhibited significantly longer colons, and less anal bleeding. Concurrently, AAT-treated mice had significantly fewer polyps, and lower numbers of large colon tumors. Immunohistochemical examinations of colon tissues showed significantly lower neutrophil counts, more granzyme B-positive but fewer MMP9 (gelatinase B)-positive cancer cells and lower numbers of apoptotic cells in mice receiving AAT therapy. The expression levels of IL4 were significantly higher while TNFA was slightly reduced in tumor tissues of AOM/DSS mice treated with AAT than in AOM/DSS mice.
CONCLUSION
Human AAT is an acute phase protein with a broad-protease inhibitory and immunomodulatory activities used as a therapeutic for emphysema patients with inherited AAT deficiency. Our results are consistent with previous findings and support an idea that AAT alone and/or in combination with available anti-cancer therapies may represent a new personalized approach for patients with colitis-induced colon cancer.
Topics: Humans; Animals; Mice; Colitis-Associated Neoplasms; Colonic Neoplasms; Colon; Colitis; Inflammatory Bowel Diseases; Azoxymethane; Dextran Sulfate; Disease Models, Animal; Mice, Inbred C57BL
PubMed: 37532996
DOI: 10.1186/s12885-023-11195-5 -
Theranostics 2024To elucidate dynamics and functions in colonic macrophage subsets, and their regulation by () and its associated metabolites in the initiation of colitis-associated...
To elucidate dynamics and functions in colonic macrophage subsets, and their regulation by () and its associated metabolites in the initiation of colitis-associated colorectal cancer (CAC). Azoxymethane (AOM) and dextran sodium sulfate (DSS) were used to create a CAC model. The tumor-suppressive effect of and variations of macrophage subsets were evaluated. Intestinal macrophages were ablated to determine their role in the protective effects of . Efficacious molecules produced by were identified by non-targeted and targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. The molecular mechanism was further verified in murine bone marrow-derived macrophages (BMDMs), macrophages derived from human peripheral blood mononuclear cells (hPBMCs), and demonstrated in CAC mice. alleviated colitis symptoms, delayed colonic tumorigenesis, and promoted phenotypic differentiation of immature inflammatory macrophages into mature homeostatic macrophages. On the contrary, the ablation of intestinal macrophages largely annulled the protective effects of . Microbial analysis of colonic contents revealed the enrichment of probiotics and the depletion of potential pathogens following supplementation. Moreover, indole-3-lactic acid (ILA) was positively correlated with in CAC mice and highly enriched in the culture supernatant of . Also, the addition of ILA directly promoted AKT phosphorylation and restricted the pro-inflammatory response of murine BMDMs and macrophages derived from hPBMCs . The effects of ILA in murine BMDMs and macrophages derived from hPBMCs were abolished by the aryl hydrocarbon receptor (AhR) antagonist CH-223191 or the AKT inhibitor MK-2206. Furthermore, ILA could protect against tumorigenesis by regulating macrophage differentiation in CAC mice; the AhR antagonist largely abrogated the effects of and ILA in relieving colitis and tumorigenesis. -mediated tryptophan metabolism ameliorates the precancerous inflammatory intestinal milieu to inhibit tumorigenesis by directing the differentiation of immature colonic macrophages.
Topics: Animals; Mice; Macrophages; Bifidobacterium breve; Indoles; Humans; Colitis; Cell Differentiation; Probiotics; Disease Models, Animal; Carcinogenesis; Colitis-Associated Neoplasms; Mice, Inbred C57BL; Colon; Dextran Sulfate; Male; Gastrointestinal Microbiome; Colorectal Neoplasms; Azoxymethane
PubMed: 38773969
DOI: 10.7150/thno.92350 -
SAGE Open Medicine 2023Pinostrobin (5-hydroxy-7-methoxyflavanone; PN) is a natural active ingredient with numerous biological activities extensively utilized in tumour chemotherapy. The...
OBJECTIVES
Pinostrobin (5-hydroxy-7-methoxyflavanone; PN) is a natural active ingredient with numerous biological activities extensively utilized in tumour chemotherapy. The present study investigates the chemo-preventive potentials of PN on azoxymethane-mediated colonic aberrant crypt foci in rats.
METHODS
Sprague Dawley rats clustered into five groups, normal control (A) and cancer controls were subcutaneously injected with normal saline and 15 mg/kg azoxymethane, respectively, and nourished on 10% tween 20 and fed on 10% tween 20; reference control (C), injected with 15 mg/kg azoxymethane and injected (intraperitoneal) with 35 mg/kg 5-fluorouracil (5-FU); D and E rat groups received a subcutaneous injection of 15 mg/kg azoxymethane and nourished on 30 and 60 mg/kg of PN, respectively.
RESULTS
The acute toxicity trial showed a lack of any abnormal signs or mortality in rats ingested with 250 and 500 mg/kg of PN. The gross morphology of colon tissues revealed significantly lower total colonic aberrant crypt foci incidence in PN-treated rats than that of cancer controls. Histological examination of colon tissues showed increased aberrant crypt foci availability with bizarrely elongated nuclei, stratified cells and higher depletion of the submucosal glands in cancer controls. PN treatment caused positive modulation of apoptotic (Bax and Bcl-2) proteins and inflammatory cytokines (TNF-α, IL-6 and IL-10). Moreover, rats fed on PN had significantly higher antioxidants (superoxide dismutase) and lower malondialdehyde concentrations in their colon tissue homogenates.
CONCLUSION
The chemoprotective efficiency of PN against azoxymethane-induced aberrant crypt foci is shown by lower aberrant crypt foci values and higher aberrant crypt foci inhibition percentage, possibly through augmentation of genes responsible for apoptotic cascade and inflammations originating from azoxymethane oxidative stress insults.
PubMed: 38078205
DOI: 10.1177/20503121231216585 -
Biomedicine & Pharmacotherapy =... Aug 2023The high prevalence of colorectal cancer (CRC) and its leading death causing rate have placed a considerable burden on patients and healthcare providers. There is a need...
The high prevalence of colorectal cancer (CRC) and its leading death causing rate have placed a considerable burden on patients and healthcare providers. There is a need for a therapy that has fewer adverse effects and greater efficiency. Zearalenone (ZEA), an estrogenic mycotoxin, has been demonstrated to exert apoptotic properties when administrated in higher doses. However, it is unclear whether such apoptotic effect remains valid in an in vivo setting. The current study aimed to investigate the effect of ZEA on CRC and its underlying mechanisms in the azoxymethane/ dextran sodium sulfate (AOM/DSS) model. Our results revealed that ZEA significantly lowered the total number of tumours, colon weight, colonic crypt depth, collagen fibrosis and spleen weight. ZEA suppressed Ras/Raf/ERK/cyclin D1 pathway, increasing the expression of apoptosis parker, cleaved caspase 3, while decreasing the expression of proliferative marker, Ki67 and cyclin D1. The gut microbiota composition in ZEA group showed higher stability and lower vulnerability in the microbial community when compared to AOM/DSS group. ZEA increased the abundance of short chain fatty acids (SCFAs) producing bacteria unidentified Ruminococcaceae, Parabacteroidies and Blautia, as well as the faecal acetate content. Notably, unidentified Ruminococcaceae and Parabacteroidies were substantially correlated with the decrease in tumour count. Overall, ZEA demonstrated a promising inhibitory effect on colorectal tumorigenesis and exhibited the potential for further development as a CRC treatment.
Topics: Humans; Animals; Mice; Colorectal Neoplasms; Zearalenone; Cyclin D1; MAP Kinase Signaling System; Colitis; Carcinogenesis; Cell Transformation, Neoplastic; Azoxymethane; Bacteria; Dextran Sulfate; Disease Models, Animal; Mice, Inbred C57BL
PubMed: 37269808
DOI: 10.1016/j.biopha.2023.114973 -
Aging Nov 2023Colorectal cancer (CRC) is one of the most common tumors of the digestive tract, with the third-highest incidence and the second-highest mortality rate among all...
Colorectal cancer (CRC) is one of the most common tumors of the digestive tract, with the third-highest incidence and the second-highest mortality rate among all malignant tumors worldwide. However, treatment options for CRC remain limited. As a complementary therapy, acupuncture or electro-acupuncture (EA) has been widely applied in the treatment of various inflammation-related diseases, such as obesity, ulcerative colitis and tumors. Although numerous pre-clinical and clinical studies have investigated the beneficial effects of acupuncture on CRC, the mechanism underlying the therapeutic action of EA is largely unknown. Evidence from previous studies has revealed that SIRT1 participates in CRC progression by activating autophagy-related miRNAs. Using azoxymethane/dextran sulfate sodium- (AOM/DSS-) induced colorectal cancer model in mice, we explored whether EA treatment can inhibit inflammation and promote autophagy via the SIRT1/miR-215/Atg14 axis. Our results showed that EA notably alleviated the CRC in mice, by decreasing the tumor number and DAI scores, inflammation, and increasing body weight of mice. Besides, EA increased the expression of SIRT1 and autophagy. Further experiments showed that SIRT1 overexpression downregulated miR-215, and promoted the expression of Atg14, whereas SIRT1 knockdown induced opposite results. In conclusion, EA can ameliorate AOM/DSS-induced CRC through regulating the SIRT1-mediated miR-215/Atg14 axis by suppressing inflammation and promoting autophagy in mice. These findings reveal a potential molecular mechanism underlying the anti-CRC effect of EA indicating that EA is a promising therapeutic candidate for CRC.
Topics: Mice; Animals; Colorectal Neoplasms; Electroacupuncture; Sirtuin 1; Inflammation; MicroRNAs; Autophagy; Mice, Inbred C57BL; Disease Models, Animal
PubMed: 38006398
DOI: 10.18632/aging.205236 -
Biomedicines Mar 2024Colorectal cancer is a global malignancy with a high incidence and mortality rate. THZ2, a small inhibitor targeted CDK7, could inhibit multiple human tumor growths...
Colorectal cancer is a global malignancy with a high incidence and mortality rate. THZ2, a small inhibitor targeted CDK7, could inhibit multiple human tumor growths including small cell lung cancer, triple-negative breast cancer, ovarian cancer. However, the effect of THZ2 on inflammation, especially on colitis-associated colorectal cancer, is still unknown. In this study, we assessed the anti-inflammatory and anti-tumor effect of THZ2 in the mouse models of dextran sulfate sodium (DSS)-induced acute colitis and azoxymethane (AOM)/DSS-induced colitis-associated colorectal cancer. We found that THZ2 ameliorated inflammatory symptoms, including bleeding and diarrhea, in mouse models of DSS-induced acute colitis and AOM/DSS-induced colorectal cancer. The results of Western blot and immunohistochemistry showed that THZ2 rescued the up-regulated expression of COX2, IL-6, β-catenin, and snail in the mouse models. Moreover, THZ2 inhibits the development of colorectal cancer in the mouse model of AOM/DSS-induced colitis-associated colorectal cancer. Generally, THZ2 not only can inhibit DSS-induced colitis, but also can hinder AOM/DSS-induced colorectal cancer.
PubMed: 38540292
DOI: 10.3390/biomedicines12030679