Cancer is considered a fatal disease caused by uncontrolled proliferation and progression of abnormal cells. The most efficient cancer therapies suppress tumor growth, prevent progression and ...metastasis, and are minimally toxic to normal cells. Natural compounds have shown a variety of chemo-protective effects alone or in combination with standard cancer therapies. Along with better understanding of the dynamic interactions between our immune system and cancer development, nutritional immunology-the use of natural compounds as immunomodulators in cancer patients-has begun to emerge. Cancer cells evolve strategies that target many aspects of the immune system to escape or even edit immune surveillance. Therefore, the immunesuppressive tumor microenvironment is a major obstacle in the development of cancer therapies. Because interaction between the tumor microenvironment and the immune system is a complex topic, this review focuses mainly on human clinical trials and animal studies, and it highlights specific immune cells and their cytokines that have been modulated by natural compounds, including carotenoids, curcumin, resveratrol, EGCG, and β-glucans. These natural compounds have shown promising immune-modulating effects, such as inhibiting myeloid-derived suppressor cells and enhancing natural killer and cytolytic T cells, in tumor-bearing animal models, but their efficacy in cancer patients remains to be determined.
Background
Neuroendocrine tumors (NETs) are rare epithelial neoplasms that arise most commonly from the gastrointestinal tract. In pediatrics, the most common site of origin is in the appendix, with ...the liver being the most common site of metastasis. Neuroendocrine tumors arising from the biliary tract are extremely rare.
Methods
We describe a case of a nine‐year‐old girl who presented with obstructive cholestasis and was found to have multiple liver masses identified on biopsy as well‐differentiated neuroendocrine tumor with an unknown primary tumor site.
Result
The patient underwent extensive investigation to identify a primary tumor site, including endoscopy, endoscopic ultrasound, and capsule endoscopy. The patient ultimately underwent definitive management with liver transplant, and on explant was discovered to have multiple well‐differentiated neuroendocrine tumors, WHO Grade 1, with extensive infiltration into the submucosa of bile duct, consistent with primary biliary tract neuroendocrine tumor.
Conclusion
Identifying the site of the primary tumor in NETs found within the liver can be challenging. To determine if an extrahepatic primary tumor exists, workup should include endoscopy, EUS, and capsule endoscopy. Children with well‐differentiated hepatic NETs, with no identifiable primary tumor, and an unresectable tumor, are considered favorable candidates for liver transplantation.
Free fatty acid receptor 2 (FFAR2, also named GPR43), is activated by short‐chain fatty acids (SCFAs), such as butyrate, that are produced when gut bacteria ferment dietary fiber. FFAR2 has been ...suggested to regulate colonic inflammation, which is a major risk factor for the development of colon cancer and is also linked to epigenetic dysregulation in colon carcinogenesis. The current study assessed whether FFAR2, acting as an epigenetic regulator, protects against colon carcinogenesis. To mimic the mild inflammation that promotes human colon cancer, we treated mice with dextran sodium sulfate (DSS) overnight, which avoids excessive inflammation but induces mild inflammation that promotes colon carcinogenesis in the ApcMin/+ and the azoxymethane (AOM)‐treated mice. Our results showed that FFAR2 deficiency promotes the development of colon adenoma in the ApcMin/+/DSS mice and the progression of adenoma to adenocarcinoma in the AOM/DSS mice. FFAR2's downstream cAMP–PKA–CREB pathway was enhanced, leading to overexpression of histone deacetylases (HDACs) in the FFAR2‐deficient mice. ChIP‐qPCR analysis revealed differential binding of H3K27me3 and H3K4me3 histone marks onto the promoter regions of inflammation suppressors (e.g., sfrp1, dkk3, socs1), resulting in decreased expression of these genes in the FFAR2‐deficient mice. Also, more neutrophils infiltrated into tumors and colon lamina propria of the FFAR2‐deficient mice. Depletion of neutrophils blocked the progression of colon tumors. In addition, FFAR2 is required for butyrate to suppress HDAC expression and hypermethylation of inflammation suppressors. Therefore, our results suggest that FFAR2 is an epigenetic tumor suppressor that acts at multiple stages of colon carcinogenesis.
What's new?
Free fatty acid receptor 2 (FFAR2) is involved in colonic inflammation. However, it remains unclear whether FFAR2 is an epigenetic regulator that suppresses colon tumorigenesis. This study suggests that loss of FFAR2 epigenetically promotes colon cancer development. The authors found in FFAR2‐deficient mice that the downstream cAMP–PKA–CREB–HDAC pathway was enhanced. H3K27me3 and H3K4me3 histone marks differentially bound onto the promoter regions of inflammation suppressors, resulting in their lower expression. More neutrophils infiltrated into tumors and colonic lamina propria. FFAR2 is required for butyrate, a natural ligand of FFAR2, to suppress HDAC expression and hypermethylation of inflammation suppressors.
•Residual tumor cellularity of pancreatic adenocarcinoma (PDAC) was measured with digital image software•Tumor cellularity of PDAC with and without neoadjuvant was analyzed and showed wide ...ranges•Patients with neoadjuvant treated tumor with measured cellularity <4% had longer overall survival than those with ≥4%•The CAP and Evans grade did not significantly correlate with overall survival•Residual tumor cellularity might correlate the best with overall survival which would support its use in tumor regression grading for pancreatic adenocarcinoma
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