Uncovering dark matter in cancer by identifying epigenetic drivers.

The complex relationship between chromatin accessibility, transcriptional regulation, and cancer transitions presents a daunting puzzle. Terekhanova et al. created a pan-cancer epigenetic and transcriptomic atlas at single-cell resolution, yielding important insights into the underlying chromatin architecture of cancer transitions and novel discoveries with the potential to advance precision medicine.

Regulator of G protein signaling 1 is a potential target in gastric cancer and impacts tumor-associated macrophages.

Regulator of G protein signaling 1 (RGS1) is closely associated with the tumor immune microenvironment and is highly expressed in various tumors and immune cells. The specific effects of RGS1 in the dynamic progression from chronic gastritis to gastric cancer have not been reported, and the role of tumor-associated macrophages (TAMs) is also unclear. In the present study, RGS1 was identified as an upregulated gene in different pathological stages ranging from chronic gastritis to gastric cancer by using Gene Expression Omnibus (GEO) screening together with pancancer analysis of The Cancer Genome Atlas and clinical prognostic analysis. The results indicated that RGS1 is highly expressed in gastric cancer and has potential prognostic value. We confirmed through in vivo experiments that RGS1 inhibited the proliferation of gastric cancer cells and promoted apoptosis, which was further corroborated by in vitro experiments. Additionally, RGS1 influenced cell migration and invasion. In our subsequent investigation of RGS1, we discovered its role in the immune response. Through analyses of single-cell and GEO database data, we confirmed its involvement in immune cell regulation, specifically TAM activation. Subsequently, we conducted in vivo and in vitro experiments to confirm the involvement of RGS1 in polarizing M1 macrophages while indirectly regulating M2 macrophages through tumor cells. In conclusion, RGS1 could be a potential target for the transformation of chronic gastritis into gastric cancer and has a measurable impact on TAMs, which warrants further in-depth research.

Global patterns of cancer transitions: A modelling study.

Cancer is a major contributor to global disease burden. Many countries experienced or are experiencing the transition that non-infection-related cancers replace infection-related cancers. We aimed to characterise burden changes for major types of cancers and identify global transition patterns. We focused on 10 most common cancers worldwide and extracted age-standardised incidence and mortality in 204 countries and territories from 1990 to 2019 through the Global Burden of Disease Study. Two-stage modelling design was used. First, we applied growth mixture models (GMMs) to identify distinct trajectories for incidence and mortality of each cancer type. Next, we performed latent class analysis to detect cancer transition patterns based on the categorisation results from GMMs. Kruskal-Wallis H tests were conducted to evaluate associations between transition patterns and socioeconomic indicators. Three distinct patterns were identified as unfavourable, intermediate and favourable stages. Trajectories of lung and breast cancers had the strongest association with transition patterns among men and women. The unfavourable stage was characterised by rapid increases in lung, breast and colorectal cancers alongside stable or decreasing burden of gastric, cervical, oesophageal and liver cancers. In contrast, the favourable stage exhibited rapid declines in most cancers. The unfavourable stage was associated with lower sociodemographic index, health expenditure, gross domestic product per capita and higher maternal mortality ratio (P < .001 for all associations). Our findings suggest that unfavourable, intermediate and favourable transition patterns exist. Countries and territories in the unfavourable stage tend to be socioeconomically disadvantaged, and tailored intervention strategies are needed in these resource-limited settings.

Urban-rural disparity in cancer mortality and changing trend in Tianjin, China, during 1999 and 2016.

OBJECTIVE: Compare the urban-rural disparity in cancer mortality and changing trend during the past 18 years in Tianjin, China. METHODS: Cancer death data were obtained from Tianjin All Cause of Death Registration System (CDRS), which covers the whole population of Tianjin. We calculated and compared the constituent ratio of cancer deaths, age-standardized mortality rate(ASR)and changing trends between urban and rural areas. RESULTS: From 1999 to 2016, a total of 245,744 cancer deaths were reported, accounting 21.7% of all deaths in Tianjin. The ASR of total cancer mortality was higher in urban areas than in rural areas. A total of 33,739 persons were avoided dying of cancers in rural area compared to the urban death level from 1999 to 2016, which was 40.1% compare to the current level of rural areas. But the gap between urban and rural areas became narrowed gradually. The urban-rural ratios (urban/rural) of total cancer mortality changed from 1.76 (125.7/71.5)[95%CI,1.67,1.84] in 1999 to 1.11 (99.6/90.0)[95%CI,1.06,1.15] in 2016. The ASR of lung, liver and esophagus cancer became higher in rural areas than in urban areas in 2016. CONCLUSION: Cancer transition was obviously occurred in Tianjin and showed different speeds and big gap between urban and rural areas. Much more attention was needed to pay in rural areas which still have increasing trends in most cancers mortality recently.

Single-cell Landscape of Malignant Transition: Unraveling Cancer Cell-of-Origin and Heterogeneous Tissue Microenvironment.

Understanding disease progression and sophisticated tumor ecosystems is imperative for investigating tumorigenesis mechanisms and developing novel prevention strategies. Here, we dissected heterogeneous microenvironments during malignant transitions by leveraging data from 1396 samples spanning 13 major tissues. Within transitional stem-like subpopulations highly enriched in precancers and cancers, we identified 30 recurring cellular states strongly linked to malignancy, including hypoxia and epithelial senescence, revealing a high degree of plasticity in epithelial stem cells. By characterizing dynamics in stem-cell crosstalk with the microenvironment along the pseudotime axis, we found differential roles of ANXA1 at different stages of tumor development. In precancerous stages, reduced ANXA1 levels promoted monocyte differentiation toward M1 macrophages and inflammatory responses, whereas during malignant progression, upregulated ANXA1 fostered M2 macrophage polarization and cancer-associated fibroblast transformation by increasing TGF-ß production. Our spatiotemporal analysis further provided insights into mechanisms responsible for immunosuppression and a potential target to control evolution of precancer and mitigate the risk for cancer development.

Banxia Xiexin Decoction delays colitis-to-cancer transition by inhibiting E-cadherin/ß-catenin pathway via Fusobacterium nucleatum FadA.

ETHNOPHARMACOLOGICAL RELEVANCE: Colitis is an important risk factor for the occurrence of colorectal cancer (CRC), and the colonization of Fusobacterium nucleatum (Fn) in the intestines accelerates this transformation process. Banxia Xiexin Decoction (BXD), originating from Shanghanlun, is a classic prescription for treating gastrointestinal diseases. Current researches indicate that BXD can effectively delay the colitis-to-cancer transition, but it is still unclear whether it can inhibit Fn colonization to achieve this delaying effect. AIM OF STUDY: This study explored the effect and mechanism of BXD in inhibiting Fn intestinal colonization to delay colitis-to-cancer transition. MATERIALS AND METHODS: We constructed a mouse model of colitis-to-cancer transition by regularly gavaging Fn combined with azoxymethane (AOM)/dextran sodium sulfate (DSS), and administered BXD by gavage. We monitored the body weight of mice, measured the length and weight of their colons, and calculated the disease activity index (DAI) score. The growth status of colon tumors was observed by hematoxylin and eosin (H&E) staining, and the changes in gut microbiota in each group of mice were detected by 16S rDNA analysis. Immunohistochemistry was used to detect the expression of E-cadherin and ß-catenin in colon tissues, and immunofluorescence was used to observe the infiltration of M2 macrophages in colon tissues. In cell experiments, we established a co-culture model of Fn and colon cancer cells and intervened with BXD-containing serum. Malignant behaviors such as cell proliferation, invasion, and migration were detected, as well as changes in their cell cycle. We examined the protein levels of E-cadherin, ß-catenin, Axin2, and Cyclin D1 in each group were detected by Western blot. We used US1 strain (fadA-) as a control and observed the effects of BXD-containing serum on Fn attachment and invasion of colon cancer cells through attachment and invasion experiments. RESULTS: BXD can inhibit the colitis-to-cancer transition in mice infected with Fn, reduce crypt structure damage, improve gut microbiota dysbiosis, upregulate E-cadherin and decrease ß-catenin expression, and reduce infiltration of M2 macrophages, thus inhibiting the process of colitis-to-cancer transition. Cell experiments revealed that BXD-containing serum can inhibit the proliferation, migration, and invasion of colon cancer cells infected with Fn and regulate their cell cycle. More importantly, we found that BXD-containing serum can inhibit the binding of Fn's FadA adhesin to E-cadherin, reduce Fn's attachment and invasion of colon cancer cells, thereby downregulating the E-cadherin/ß-catenin signaling pathway. CONCLUSIONS: These findings show that BXD can inhibit Fn colonization by interfering with the binding of FadA to E-cadherin, reducing the activation of the E-cadherin/ß-catenin signaling pathway, and ultimately delaying colitis-to-cancer transition.

Pathogenesis from Inflammation to Cancer in NASH-Derived HCC.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and one of the deadliest cancers worldwide. As opposed to the majority of patients with HCC, approximately 20-30% of cases of non-alcoholic steatohepatitis (NASH)-derived HCC develop malignant tumours in the absence of liver cirrhosis. NASH is characterized by metabolic dysregulation, chronic inflammation and cell death in the liver, which provide a favorable setting for the transformation of inflammation into cancer. This review aims to describe the pathogenesis and the underlying mechanism of the transition from inflammation to cancer in NASH.

Immune Cell Types and Secreted Factors Contributing to Inflammation-to-Cancer Transition and Immune Therapy Response.

Although chronic inflammation increases many cancers' risk, how inflammation facilitates cancer development is still not well studied. Recognizing whether and when inflamed tissues transition to cancerous tissues is of utmost importance. To unbiasedly infer molecular events, immune cell types, and secreted factors contributing to the inflammation-to-cancer (I2C) transition, we develop a computational package called "SwitchDetector" based on liver, gastric, and colon cancer I2C data. Using it, we identify angiogenesis associated with a common critical transition stage for multiple I2C events. Furthermore, we infer infiltrated immune cell type composition and their secreted or suppressed extracellular proteins to predict expression of important transition stage genes. This identifies extracellular proteins that may serve as early-detection biomarkers for pre-cancer and early-cancer stages. They alone or together with I2C hallmark angiogenesis genes are significantly related to cancer prognosis and can predict immune therapy response. The SwitchDetector and I2C database are publicly available at www.inflammation2cancer.org.