The role of cancer-associated fibroblasts in breast cancer metastasis

Breast cancer deaths are primarily caused by metastasis. There are several treatment options that can be used to treat breast cancer. There are, however, a limited number of treatments that can either prevent or inhibit the spread of breast tumor metastases. Thus, novel therapeutic strategies are needed. Studies have increasingly focused on the importance of the tumor microenvironment (TME) in metastasis of breast cancer. As the most abundant cells in the TME, cancer-associated fibroblasts (CAFs) play important roles in cancer pathogenesis. They can remodel the structure of the extracellular matrix (ECM) and engage in crosstalk with cancer cells or other stroma cells by secreting growth factors, cytokines, and chemokines, as well as components of the ECM, which assist the tumor cells to invade through the TME and cause distant metastasis. Clinically, CAFs not only foster the initiation, growth, angiogenesis, invasion, and metastasis of breast cancer but also serve as biomarkers for diagnosis, therapy, and prediction of prognosis. In this review, we summarize the biological characteristics and subtypes of CAFs and their functions in breast cancer metastasis, focusing on their important roles in the diagnosis, prognosis, and treatment of breast cancer. Recent studies suggest that CAFs are vital partners of breast cancer cells that assist metastasis and may represent ideal targets for prevention and treatment of breast cancer metastasis

Influence of Climatic Factors on Lightning Fires in the Primeval Forest Region of the Northern Daxing’an Mountains, China

Forest fires lead to permafrost degradation and localized drought, and regional droughts increase the probability of forest fires, leading to a positive feedback loop between climate change and fires. However, the relationship between fire occurrence and climatic factors change is unclear for boreal forests, which represent the largest land-based biome and stock of carbon. Here, we analyzed the relationship between lightning fire occurrence and meteorological and topographic factors based on the fire frequency, burned area, and meteorological data from the primeval forest region of the northern Daxing’an Mountains in China. We found that lightning fires occurred most frequently at an altitude of 600 to 700 m. From 1999 to 2019, the frequency of lightning fires showed an overall upward trend, whereas the affected area had no obvious change. It can be attributed to fire suppression efforts and greatly increased investment in fire prevention in China. Snow cover had a strong regulatory effect on the start and end dates of lightning fires for seasonal cycle. The frequency of lightning fires was positively correlated with the average temperature, maximum temperature, and surface evaporation and negatively correlated with precipitation and surface soil moisture (0–10 cm). The result will be useful in the spatially assessment of fire risk, the planning and coordination of regional efforts to identify areas at greatest risk, and in designing long-term lightning fires management strategies

Influence of Climatic Factors on Lightning Fires in the Primeval Forest Region of the Northern Daxing’an Mountains, China

Forest fires lead to permafrost degradation and localized drought, and regional droughts increase the probability of forest fires, leading to a positive feedback loop between climate change and fires. However, the relationship between fire occurrence and climatic factors change is unclear for boreal forests, which represent the largest land-based biome and stock of carbon. Here, we analyzed the relationship between lightning fire occurrence and meteorological and topographic factors based on the fire frequency, burned area, and meteorological data from the primeval forest region of the northern Daxing’an Mountains in China. We found that lightning fires occurred most frequently at an altitude of 600 to 700 m. From 1999 to 2019, the frequency of lightning fires showed an overall upward trend, whereas the affected area had no obvious change. It can be attributed to fire suppression efforts and greatly increased investment in fire prevention in China. Snow cover had a strong regulatory effect on the start and end dates of lightning fires for seasonal cycle. The frequency of lightning fires was positively correlated with the average temperature, maximum temperature, and surface evaporation and negatively correlated with precipitation and surface soil moisture (0–10 cm). The result will be useful in the spatially assessment of fire risk, the planning and coordination of regional efforts to identify areas at greatest risk, and in designing long-term lightning fires management strategies

Surgical Outcomes and Prognostic Factors of G3 Pancreatic Neuroendocrine Carcinomas: A Consecutive Analysis Based on Previous Study Results

In 2017, the World Health Organization (WHO) officially defined pancreatic neuroendocrine neoplasms into well-differentiated tumors, namely G1/G2/G3 pancreatic neuroendocrine tumors, and poorly differentiated carcinomas referring to G3 pancreatic neuroendocrine carcinomas (p-NECs). However, the surgical outcomes and prognostic factors of G3 p-NECs are still unclear. Methods: We retrospectively collected and analyzed the data of eligible patients with G3 p-NECs defined by the WHO 2017 grading classification. Results: We eventually identified 120 patients with G3 p-NECs, including 72 females and 48 males, with a median age of 53 y. The 3-year overall survival (OS) of G3 p-NECs by Kaplan–Meier method was 37.3%. The 3-year OS for functional G3 p-NECs was 57.4%, which was statistically longer than 23.0% of non-functional ones (p = 0.002). Patients with surgical resection presented a significantly better 3-year OS than those with palliative operation (43.3% vs. 13.1%; p p p = 0.013), vascular infiltration (p = 0.039), lymph node involvement (p = 0.024), and distant metastasis (p = 0.016) were independent predictors of poor outcome for patients with surgically treated G3 p-NECs. Conclusion: Our data in the present analysis indicated that patients with G3 p-NECs could significantly benefit from surgical resection. Meanwhile, vascular infiltration, lymph node involvement, and distant metastasis were independent predictors of poor outcome for these patients

Spatial-Temporal Characteristics and Driving Forces of Aboveground Biomass in Desert Steppes of Inner Mongolia, China in the Past 20 Years

The desert steppe serves as a transitional zone between grasslands and deserts, and long-term monitoring of aboveground biomass (AGB) in the desert steppe is essential for understanding grassland changes. While AGB observation techniques based on multisource remote-sensing data and machine-learning algorithms have been widely applied, research on monitoring methods specifically for the desert steppe remains limited. In this study, we focused on the desert steppe of Inner Mongolia, China, as the study area and used field sampling data, MODIS data, MODIS-based vegetation indices (VI), and environmental factors (topography, climate, and soil) to compare the performance of four commonly used machine-learning algorithms: multiple linear regression (MLR), partial least-squares regression (PLS), random forest (RF), and support vector machine (SVM) in AGB estimation. Based on the optimal model, the spatial–temporal characteristics of AGB from 2000 to 2020 were calculated, and the driving forces of climate change and human activities on AGB changes were quantitatively analyzed using the random forest algorithm. The results are as follows: (1) RF demonstrated outstanding performance in terms of prediction accuracy and model robustness, making it suitable for AGB estimation in the desert steppe of Inner Mongolia; (2) VI contributed the most to the model, and no significant difference was found between soil-adjusted VIs and traditional VIs. Elevation, slope, precipitation, and temperature all had positive effects on the model; (3) from 2000 to 2020, the multiyear average AGB in the study area was 58.34 g/m2, exhibiting a gradually increasing distribution pattern from the inner region to the outer region (from north to south); (4) from 2000 to 2020, the proportions of grassland with AGB slightly and significantly increasing trend in the study area were 87.08% and 5.13%, respectively, while the proportions of grassland with AGB slightly and significantly decreasing trend were 7.76% and 0.05%, respectively; and (5) over the past 20 years, climate change, particularly precipitation, has been the primary driving force behind AGB changes of the study area. This research holds reference value for improving desert steppe monitoring capabilities and the rational planning of grassland resources

Gemcitabine treatment induces endoplasmic reticular (ER) stress and subsequently upregulates urokinase plasminogen activator (uPA) to block mitochondrial-dependent apoptosis in Panc-1 cancer stem-like cells (CSCs)

<div><p>Background</p><p>Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with poor survival rates. The presence of cancer stem-like cells (CSCs) is believed to be among the underlying reasons for the aggressiveness of PDAC, which contributes to chemoresistance and recurrence. However, the mechanisms that induce chemoresistance and inhibit apoptosis remain largely unknown.</p><p>Methods</p><p>We used serum-free medium to enrich CSCs from panc-1 human pancreatic cancer cells and performed sphere formation testing, flow cytometry, quantitative reverse transcription polymerase chain reaction (RT-qPCR) and semi-quantitative western blotting to confirm the stemness of panc-1 CSCs. Hallmarks of endoplasmic reticulum (ER) stress, including IRE1, PERK, ATF4, ATF6α, GRP78 and uPA expression, were detected after gemcitabine treatment. Effects of gemcitabine-induced uPA expression on cell invasion, sphere formation, colony formation and gemcitabine sensitivity were detected. Electrophoretic mobility shift assays (EMSAs) and RNA-immunoprecipitation (RIP) were performed to detect interaction between the uPA mRNA 3’-UTR and mutant p53-R273H expressed by panc-1 CSCs. The effects of upregulated uPA by gemcitabine on apoptosis were detected by Annexin V-FITC/PI staining, and the impact of uPA on small molecule CP-31398-restored mutant p53 transcriptional activity was measured by a luciferase reporter assay.</p><p>Results</p><p>Enriched panc-1 CSCs expressing high levels of CD44 and CD133 also produced significantly higher amounts of Oct4 and Nanog. Compared with panc-1 cells, panc-1 CSCs presented chemoresistance to gemcitabine. ER stress gene detections demonstrated effects of gemcitabine-induced ER stress on both the pro-apoptotic and pro-survival branches. ER stress-induced ATF6α upregulated level of uPA by transcriptionally activating GRP78. Gemcitabine-induced uPA promoted invasion, sphere formation and colony formation and attenuated apoptosis induced by gemcitabine in panc-1 CSCs, depending on interaction with mutant p53-R273H. Upregulation of uPA abolished CP-31398-mediated restoration of mutant p53 transcriptional activity in panc-1 CSCs.</p><p>Conclusion</p><p>Gemcitabine treatment induced ER stress and promoted mutant p53-R273H stabilization via transcriptionally activated uPA which may contribute to chemoresistance to gemcitabine. Notably, upregulation of uPA by gemcitabine treatment may lead to the failure of CP-31398; thus, a novel strategy for modulating mutant p53 function needs to be developed.</p></div

Enrichment and characterization of human pancreatic CSCs from human pancreatic cancer cell line Panc-1.

<p>(A) Sphere formation of Panc-1 CSCs at day 7, 14 and 21. (B) Self-renewal capacity of Panc-1 CSCs were tested using serial replating assay. (C) Panc-1 CSCs were analyzed by folw cytometry using antibody against CD24, CD44, and CD133. (D) Expression of stem cell markers. The expression of CD24, CD44, CD133, Oct4, and Nanog was measured by RT-qPCR. Data represent mean±SD (left panel). protein levels were assessed by semi-quantitative Western blot (righ panel). (E) Gemcitabine sensitivity of Panc-1 cells or Panc-1 CSCs were assessed. *P<0.05; **P<0.01.</p

uPA induced by Gemcitabine binds specifically to P53-R273H and partially promoted mitochondrial-dependent apoptosis.

<p>(A) RNA-IP assay was performed to confirm the binding of uPA mRNA 3’UTR to P53-R273H in Panc-1 CSCs. (B) EMSA assay was employed for confirming the direct and specific interaction between P53-R273H and fragment of uPA mRNA 3’UTR. (C) The mRNA (left panel) and protein (right panel) levels of uPA after p53 knockdown were measured. (D) The mRNA (left panel) and protein (right panel) levels of P53-R273H after uPA knockdown were measured. (E) The apoptotic condition was detected by flow cytometry using Annexin V-FITC/PI staining, after uPA or P53 knockdown. Caspase 3/7 activity (F) and cleaved PARP-1 (G) were analyzed for determine whether apoptosis induced is dependent on mitochondria. *P<0.05.</p

uPA expression attenuates the restorating effect of CP-31398 on mutant P53-R273H.

<p>(A) Confirmation of the restorating effect of 5, 10, 20, and 40 ug/ml CP-31398 on transcriptional activity of mutant p53-R273H. (B) Gemcitabine treatment abolished the restoration of CP-31398 on mutant P53-R273H. Upregulated uPA by LV-uPA introduction (C) or downregulated uPA by LV-uPA KD (D) at different MOI affected the transcriptional activity of mutant P53-R273H restored by CP-31398 treatment. *P<0.05.</p