Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease that typically features a dramatic desmoplastic reaction, especially fibroblasts. The roles of cancer-associated fibroblasts (CAFs) in PDAC have received more attention in recent years. As increasing evidence suggests the heterogeneity of CAFs in PDAC, different CAF subtypes have been shown to support tumor growth, while others suppress cancer proliferation. Myofibrotic CAFs (myCAFs) show alpha-smooth muscle actin (α-SMA)high interleukin-6 (IL-6)low myofibroblastic features, are activated by direct contact with tumor cells, and are located in the periglandular region. Inflammatory CAFs (iCAFs) show α-SMAlow IL-6high inflammatory features, are activated by paracrine factors secreted from tumor cells, and are located away from cancer cells. Antigen-presenting CAFs (apCAFs) show major histocompatibility complex II (MHC II) family genes that are highly expressed. CAFs have also been gradually explored as diagnostic and prognostic markers in pancreatic cancer. Targeted therapy of CAFs in PDAC has gradually attracted attention. With the deepening of related studies, some meaningful positive and negative results have surfaced, and CAFs may be the key to unlocking the door to pancreatic cancer treatment. Our review summarizes recent advances in the heterogeneity, function, and markers of CAFs in pancreatic cancer, as well as research and treatment targeting CAFs in pancreatic cancer.

Background and Purpose: Gut microbiota dysbiosis induced by acute pancreatitis (AP) exacerbates pancreatic injury and systemic inflammatory responses. The alleviation of gut microbiota dysbiosis through faecal microbiota transplantation (FMT) is considered a potential strategy to reduce tissue damage and inflammation in many clinical disorders. Here, we aim to investigate the effect of gut microbiota and microbiota-derived metabolites on AP and further clarify the mechanisms associated with pancreatic damage and inflammation. Experimental Approach: AP rat and mouse models were established by administration of caerulein or sodium taurocholate in vivo. Pancreatic acinar cells were exposed to caerulein and lipopolysaccharide in vitro to simulate AP. Key Results: Normobiotic FMT alleviated AP-induced gut microbiota dysbiosis and ameliorated the severity of AP, including mitochondrial dysfunction, oxidative damage and inflammation. Normobiotic FMT induced higher levels of NAD + (nicotinamide adenine dinucleotide)-associated metabolites, particularly nicotinamide mononucleotide (NMN). NMN administration mitigated AP-mediated mitochondrial dysfunction, oxidative damage and inflammation by increasing pancreatic NAD + levels. Similarly, overexpression of the NAD + -dependent mitochondrial deacetylase sirtuin 3 (SIRT3) alleviated the severity of AP. Furthermore, SIRT3 deacetylated peroxiredoxin 5 (PRDX5) and enhanced PRDX5 protein expression, thereby promoting its antioxidant and anti-inflammatory activities in AP. Importantly, normobiotic FMTmediated NMN metabolism induced SIRT3-PRDX5 pathway activation during AP. Conclusion and Implications: Gut microbiota-derived NMN alleviates the severity of AP by activating the SIRT3-PRDX5 pathway. Normobiotic FMT could be served as a potential strategy for AP treatment.

Chronic pancreatitis (CP) is described as progressive inflammatory fibrosis of pancreas, accompanied with irreversible impaired endocrine and exocrine insufficiency. Pancreatic stellate cells (PSCs) are widely distributed in the stroma of the pancreas and PSCs activation has been shown as one of the leading causes for pancreatic fibrosis. Our previous study has revealed that autophagy is dramatically activated in CP tissues, which facilitates PSCs activation and pancreatic fibrosis. Long non-coding RNAs (LncRNAs) have been recognized as crucial regulators for fibrosis-related diseases. LncRNAs interact with RNA binding protein or construct competitive endogenous RNA (ceRNA) hypothesis which elicited the fibrotic processes. Until now, the effects of lncRNAs on PSCs activation and pancreatic fibrosis have not been clearly explored. In this study, a novel lncRNA named Lnc-PFAR was found highly expressed in mouse and human CP tissues. Our data revealed that Lnc-PFAR facilitates PSCs activation and pancreatic fibrosis via RB1CC1-induced autophagy. Lnc-PFAR reduces miR-141 expression by suppressing pre-miR-141 maturation, which eventually upregulates the RB1CC1 and fibrosis-related indicators expression. Meanwhile, Lnc-PFAR enhanced PSCs activation and pancreatic fibrosis through trigging autophagy. Our study interrogates a novel lncRNA-induced mechanism in promoting the development of pancreatic fibrosis, and Lnc-PFAR is suggested to be a prospective therapeutic target in clinical scenarios.

Pancreatic ductal adenocarcinoma (PDAC) presents with high mortality and short overall survival. Cancer‐associated fibroblasts (CAFs) act as refuge for cancer cells in PDAC. Mechanisms of intracelluar communication between CAFs and cancer cells need to be explored. Long noncoding RNAs (lncRNAs) are involved in the modulation of oncogenesis and tumor progression of PDAC; however, specific lncRNAs and their mechanism of action have not been clarified clearly in tumoral microenvironment. This work aims to identify novel lncRNAs involved in cellular interaction between cancer cells and CAFs in PDAC. To this end, differentially expressed lncRNAs between long‐term and short‐term survival PDAC patients are screened. Lnc‐FSD2‐31:1 is found to be significantly increased in long‐term survival patients. This work then discovers that tumor‐derived lnc‐FSD2‐31:1 restrains CAFs activation via miR‐4736 transported by extracellular vesicles (EVs) in vitro and in vivo. Mechanistically, EVs‐derived miR‐4736 suppresses autophagy and contributes to CAFs activation by targeting ATG7. Furthermore, blocking miR‐4736 suppresses tumor growth in genetically engineered KPC (LSL‐KrasG12D/+, LSL‐Trp53R172H/+, and Pdx‐1‐Cre) mouse model of PDAC. This study demonstrates that intratumoral lnc‐FSD2‐31:1 modulates autophagy in CAFs resulting in their activation through EVs‐derived miR‐4736. Targeting miR‐4736 may be a potential biomarker and therapeutic target for PDAC.

Glioma is the most common primary brain tumor in adults and the second most common malignant tumor in children. Aberrant expression of signal transducer and activator of transcription 1 (STAT‑1) and p53 are known to affect the occurrence and progression of malignant tumors. The aim of the present study was to investigate the expression of STAT‑1 and mutant p53 gene, as well as their correlation, in patients with glioma. The present study included 50 patients who underwent glioma resection at the First Affiliated Hospital of Inner Mongolia Medical University between December 2007 and December 2011, and 10 patients with acute cerebral contusion who underwent intracerebral hematoma removal at the same hospital between January 2013 and January 2014. The expression of STAT‑1 and mutant p53 protein in patients with different grades of glioma was assessed by immunohistochemistry. Spearman's correlation coefficient was employed to examine the correlation between STAT‑1 and the grade of glioma, and mutant p53 expression. The results demonstrated that the mean expression of STAT‑1 in glioma was significantly lower compared with normal brain tissue (P<0.05). However, there was no significant difference in the STAT‑1 positive expression rate between the two groups (χ2=1.38, P>0.05). The expression score (P<0.05) and positive expression rate (χ2=31.27, P<0.05) of mutant p53 in glioma was significantly higher compared with those in normal brain tissue. Statistical analysis revealed a negative correlation between STAT‑1 expression and the grade of glioma (r=‑0.767, P<0.05). In addition, mutant p53 expression was negatively correlated with STAT‑1 expression in glioma (r=‑0.876, P<0.05). The observed negative correlation between STAT‑1 and the pathological grade of glioma suggested an association between STAT‑1 and the occurrence and development of glioma, thus revealing the potential of STAT‑1 as a diagnostic biomarker and therapeutic target for glioma.

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma, accounting for approximately 80% of cases. Although most patients in the early stages of ccRCC can be cured by surgery, ccRCC is often in the advanced stage when patients are diagnosed, with >30% of the patients presenting with distant metastases at the time of diagnosis. For ccRCC patients with distant metastases, the 5-year survival is only 12%. Immunotherapy selectively corrects tumor microenvironment (TME) immunity, which is of great significance for patients with advanced ccRCC.Nevertheless, only a small minority respond well to current immunotherapy treatments. Therefore, it is essential to continue to look for other targets for immunotherapy. Siglec-15, which contains a sialic acid-binding immunoglobulin lectin, has attracted much interest in more recent years as a potential new target for immunotherapy, and drugs targeting Siglec-15 are under development. With systemic or lineage-specific gene ablation in mice, previous studies reported Siglec-15 was mutually exclusive to the B7-H1/PD-1 pathway. [1] However, the expression of Siglec-15 in ccRCC has rarely been evaluated, especially at the translation level. Therefore, this study aimed to explore Siglec-15 expression at both the transcriptional and translational levels and its role in clinicopathological prognostic parameters in ccRCC.

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Previous studies have demonstrated that direct targeting of interstitial cancer-associated fibroblasts (CAF) and tumor fibrosis alone seemed to be an unpromising treatment option for malignant tumors. Therefore, it is necessary to further explore the mechanism of the influence of collagen and tumor fibrosis on the biological behavior of malignant tumors. The current study aimed to explore the effect of intratumor fibrosis on the prognosis of renal clear cell carcinoma (ccRCC) and its mechanism. With the bioinformatic analysis of The Cancer Genome Atlas (TCGA) database (n = 537), the study showed that high Collagen type I α 1 (COL1A1) mRNA expression indicated the poor prognosis of ccRCC patients compared with low expression ones. We further used the Two-photon-excited fluorescence (TPEF)/second harmonic generation (SHG) microscopy to determine the intratumor fibrosis of 68 patients with surgical resection of ccRCC and confirmed that a high fibrosis level in the tumor was associated with a poor prognosis compared with patients with low expression (Progression-Free Survival: p = 0.030). We further measured the protein chips of 640 cytokines in ccRCC specimens and found that several cytokines, including prolactin (PRL), were associated with the degree of fibrosis in the tumor, as confirmed by the prolactin receptor (PRLR) immunohistochemical method. In addition, the study showed that PRLR expression decreased significantly in the ccRCC compared with adjacent normal tissue (p &lt; 0.05). Our research shows that low expression of PRLR predicted the poor survival of the patient. We used the Cell Counting Kit-8 experiment, the transwell and the plate clone formation assay to evaluate the role of PRL in the 7860 and the ACHN cell lines. We found that PRL promoted ccRCC cell proliferation and migration. JAK-STAT3 activation was found in the high prolactin expression group by mass spectrum analysis. This study delineated the fibrosis-based tumor microenvironment characteristics of ccRCC. PRL/PRLR may be involved in the fibrosis process and are essential prognostic risk factors for ccRCC.