Invasion Metastasis Research Articles

Clinicopathological characteristics of endometrial carcinomas according to DNA mismatch repair protein status

DNA mismatch repair protein deficiency (MMRd) in endometrial carcinoma is associated with the risk of Lynch syndrome and response to immune checkpoint inhibitors. It is also related to microsatellite instability and corresponds to a molecular subtype of endometrial tumor with an unclear prognosis. Here, we evaluated the clinicopathological characteristics and prognosis of 312 consecutive endometrial carcinoma cases submitted to complete surgical staging at a single institution. We compared MMRd and mismatch repair protein–proficient (MMRp) tumors and examined the effects of the MMR protein loss type (MLH1/PMS2 vs. MSH2/MSH6) and influence of L1CAM and p53 expression. The median follow-up period was 54.5 (range, 0–120.5) months. No difference was observed between MMRd [n = 166 (37.2%)] and MMRp [n = 196 (62.8%)] cases in terms of age, body mass index, FIGO stage, tumor grade, tumor size, depth of myometrial infiltration, or lymph node metastasis. More MMRd than MMRp tumors had endometrioid histology (87.9% vs. 75.5%) and despite MMRd had more lymphovascular space invasion (LVSI; 27.2% vs. 16.9%), they presented fewer recurrences and no difference in lymph node metastasis and disease-related death. Relative to those with MLH1/MSH6 loss, tumors with MSH2/MSH6 loss were diagnosed at earlier FIGO stages, were smaller, and had less ≥50% myometrial invasion, LVSI and lymph node metastasis. Outcomes, however, did not differ between these groups. L1CAM positivity and mutation-type p53 expression were more common in MMRp than in MMRd tumors and did not differ between the MLH1/PMS2 and MSH2/MSH6 loss groups. In the entire cohort, L1CAM and mutation p53 expression were associated with worse prognosis, but only non-endometrioid histology, FIGO stage III/IV, and deep myometrial infiltration were significant predictors. In the subgroup of endometrioid carcinomas, only FIGO stage III/IV was associated with poor outcomes. The risk of lymph node metastasis was associated with tumor size, non-endometrioid histology, and multifocal LVSI. For MMRd tumors, only tumor size and myometrial invasion depth were predictive of lymph node involvement. In our cohort, MMRd tumors were associated with greater recurrence-free, but not overall, survival. The precise identification of MMRd status, present in a substantial proportion of endometrial cancer cases, is a challenge to be overcome for proper patient management. MMRd status serves as a marker for Lynch syndrome, and a significant number of these tumors are high risk and candidate to immunotherapy.

A prospective, open-label, randomized, controlled trial of radiofrequency ablation versus stereotactic body radiation therapy for recurrent small hepatocellular carcinoma.

4096 Background: Effective treatments are urgently needed to improve the prognosis of patients with recurrent hepatocellular carcinoma (HCC). Previous studies demonstrated that both radiofrequency ablation (RFA) and stereotactic body radiation therapy (SBRT) were promising therapies for recurrent small HCC. This trial was designed to compare the efficacy and safety of RFA versus SBRT in patients with recurrent small HCC. Methods: This is a prospective, open label, randomized controlled trial, in which patients aged between 18 and 75 years with recurrent small HCC (occurred more than 3 months after hepatectomy or RFA, a solitary HCC ≤5.0 cm in diameter without vascular invasion or extrahepatic metastasis), KPS score ≥90, Child-Pugh score ≤6, adequate organ function, and estimated life expectancy ≥6 months were considered eligible. All patients were assigned 1:1 to RFA or SBRT group, and stratification was performed according to tumor size (≤ 2.0 cm or 2.1-5.0 cm). The primary endpoint was 2-year local progression-free survival. Secondary endpoints were progression-free survival, locoregional control, overall survival, and safety. Results: A total of 170 patients were recruited during August 2019 to May 2022 (83 in RFA arm and 87 in SBRT arm). In the ITT population, median age was 56 (range, 33-75) and 15 were female. Baseline characteristics were well balanced between treatment arms. Adverse events occurred in RFA and SBRT were mainly grade 1 or grade 2 in severity, and were gastrointestinal and constitutional symptoms, or abnormal laboratory investigations. The most common adverse events were bilirubin increase（14.6%）and AST increase (13.3%) in RFA group vs ALT increase (20.0%) and AST increase (15.3%) in SBRT group. No Grade 3-4 adverse events or mortality were noted. Late adverse events were hardly observed after 3 months. The follow-up of survival data is ongoing. Conclusions: Both RFA and SBRT are tolerable and safe for patients with recurrent small HCC. This randomized controlled trial will report the survival outcomes in 2024, which will make an important contribution in clinical decision-making for recurrent small HCC. Clinical trial information: NCT04047173 .

CD44-positive Cancer Stem-like Cells as a Potential Source of Peritoneal Metastasis After Surgery.

The role of CD44 in gastric cancer-derived peritoneal metastasis is currently unknown. It was previously shown that viable, tumorigenic cancer cells are spilled into the peritoneal cavity during surgery, providing a potential cause of peritoneal recurrence after surgery. The purpose of this study was to elucidate the mechanism of peritoneal metastasis of gastric cancer through the expression of CD44 and to propose a method for preventing peritoneal recurrence. Gastric cancer cell line MKN-45 was sorted into CD44+ and CD44- cells and then injected intraperitoneally into NOD/ShiJic-scidJcl mice. Differences in tumor-initiating capacity between the two groups were assessed using in vivo limiting dilution assays. Tumors harvested from both groups were examined for CD44 and ALDH1A1 expression using immunohistochemistry. The effects of CD44 blockade with anti-CD44 antibody on cell invasion and peritoneal metastasis formation in vivo were assessed. CD44+ cells showed significantly higher efficiency in initiating peritoneal tumor than CD44- cells. Blockade of CD44 significantly reduced peritoneal dissemination of CD44+ cells in vivo, indicating that the CD44 function of intraperitoneally disseminated cancer cells helped promote the formation of peritoneal metastasis. The margin of established tumors showed clusters of cells co-expressing CD44 and ALDH1A1. Peritoneally administered CD44- cells resulted in peritoneal metastases consisting of CD44+ and CD44- cancer cells. CD44 expressing cells are a potential source of peritoneal metastasis after surgery and could be a promising target for preventing peritoneal recurrence.

Four Birds with One Stone: A Multifunctional Polypeptide Nanocomposite to Unify Ferroptosis, Nitric Oxide, and Photothermia for Amplifying Antitumor Immunity

AbstractTumor metastasis and relapse mainly results in therapy failure and becomes a big challenge in oncology. Immunogenic cell death (ICD) of tumors mediated immunotherapy (IT) is attracting widely for solving that problem although achieving sufficient ICD and strong immune response is challenging for nanoparticles‐based cancer IT. Herein, a multifunctional polypeptide coordinate nanocomposite that possesses near infrared photothermia (PT) and responsive releases of nitric oxide (NO) and iron ions is constructed, which synergistically kills cancer cells and highly prohibits metastatic 4T1 cells invasion and migration by PT‐boosted NO release and ferroptosis (FT). Remarkably, triple FT‐NO‐PT treatment amplifies the ICD effects and outperforms combo/monotherapy FT‐PT and FT in cancer cells and tumors, which further activates dendritic cells maturation, and primed CD4+T and CD8+T cells immune responses and memory effects, playing four birds with one stone (i.e., FT‐NO‐PT‐IT). The PCSFG‐based FT‐NO‐PT not only fully eradicates 4T1 primary tumors, but also induces strong ICD, immune priming, and memory effects to reject rechallenged 4T1 tumors and inhibit malignant tumor metastasis, demonstrating synergistic amplified ICD effects with strong cell immunities and memory effects by a unified FT‐NO‐PT‐IT.

AMIGO2 expression as a predictor of recurrence in cervical cancer with intermediate risk.

Patients with recurrent cervical cancer have limited treatment options and are often considered to be incurable. Since the expression of amphoterin-induced gene and open reading frame 2 (AMIGO2) in clinical samples is a prognostic factor for colorectal cancer and gastric cancer, the present aimed to elucidate whether it is also a prognostic factor for cervical cancer. Patients with primary cervical cancer who underwent radical hysterectomy or radical trachelectomy at our institution (Faculty of Medicine, Tottori University, Yonago, Japan) between September 2005 and October 2016 were retrospectively collected. Immunohistochemical analysis using a specific antibody against AMIGO2 was performed on 101 tumor samples, and the clinical characteristics, disease-free survival (DFS) and overall survival (OS) of the patients were examined. Patients in the AMIGO2-high group had a shorter 5-year DFS and OS than those in the AMIGO2-low group (P<0.001). Furthermore, AMIGO2 was an independent prognostic factor for DFS in multivariate analysis (P=0.0012). Patients in the AMIGO2-high group exhibited obvious recurrence compared with those in the AMIGO2-low group in the high-(P=0.03) and intermediate-risk groups (P=0.003). Positive lymph node metastasis, and parametrial, stromal and lymph vascular space invasion were significantly more common in AMIGO2-high patients. Taken together, AMIGO2 expression may be a predictive marker of recurrence for cervical cancer. In particular, it may be an indicator to determine the need for postoperative adjuvant therapy in intermediate-risk group patients.

Phosphorylation of IWS1 by AKT maintains liposarcoma tumor heterogeneity through preservation of cancer stem cell phenotypes and mesenchymal-epithelial plasticity

Chemotherapy remains the mainstay of treatment for patients with advanced liposarcoma (LPS), but response rates are only 25% and the overall survival at 5 years is dismal at 20–34%. Translation of other therapies have not been successful and there has been no significant improvement in prognosis for nearly 20 years. The aberrant activation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway has been implicated in the aggressive clinical behavior LPS and in resistance to chemotherapy, but the precise mechanism remains elusive and efforts to target AKT clinically have failed. Here we show that the AKT-mediated phosphorylation of the transcription elongation factor IWS1, promotes the maintenance of cancer stem cells in both cell and xenograft models of LPS. In addition, phosphorylation of IWS1 by AKT contributes to a “metastable” cell phenotype, characterized by mesenchymal/epithelial plasticity. The expression of phosphorylated IWS1 also promotes anchorage-dependent and independent growth, cell migration, invasion, and tumor metastasis. In patients with LPS, IWS1 expression is associated with reduced overall survival, increased frequency of recurrence, and shorter time to relapse after resection. These findings indicate that IWS1-mediated transcription elongation is an important regulator of human LPS pathobiology in an AKT-dependent manner and implicate IWS1 as an important molecular target to treat LPS.

Exploring the Potential Driver Gene Mutations That Promote Renal Cancer Cell Metastasis and Implantation Based on Circulating Tumor Cells Culture.

Studies have shown that the circulating tumor cell (CTC) is a necessary condition for the invasion and distant metastasis of renal cell carcimona (RCC). However, few CTCs-related gene mutations have been developed which could promote the metastasis and implantation of RCC. The objective of this study is to explore the potential driver gene mutations that promote RCC metastasis and implantation based on CTCs culture. Fifteen patients with primary mRCC and three healthy subjects were included, and peripheral blood was obtained. After the preparation of synthetic biological scaffolds, peripheral blood CTCs were cultured. Successful cultured CTCs were applied to construct CTCs-derived xenograft (CDX) models, followed by DNA extraction, whole exome sequencing (WES) and bioinformatics analysis. Synthetic biological scaffolds were constructed based on previously applied techniques, and peripheral blood CTCs culture was successfully performed. We then constructed CDX models and performed WES, and explored the potential driver gene mutations that may promote RCC metastasis and implantation. Bioinformatics analysis showed that KAZN and POU6F2 may be closely related to the prognosis of RCC. We successfully performed the culture of peripheral blood CTCs and, on this basis we initially explored the potential driver mutations for the metastasis and implantation of RCC.

Induction of perineural invasion in salivary adenoid cystic carcinoma by circular RNA RNF111.

Local recurrence, distant metastasis, and perineural invasion (PNI) viciously occur in salivary adenoid cystic carcinoma (SACC), resulting in a poor prognosis. This study aimed to explore the mechanism by which circular RNA RNF111 (circ-RNF111) regulates PNI in SACC by targeting the miR-361-5p/high mobility group box 2 (HMGB2) axis. Circ-RNF111 and HMGB2 were highly expressed in SACC specimens, while miR-361-5p was underexpressed. Functional experiments showed that ablating circ-RNF111 or promoting miR-361-5p hindered the biological functions and PNI of SACC-LM cells. HMGB2 overexpression induced the reversal of SACC-LM cell biological functions and PNI caused by circ-RNF111 knockout. Furthermore, reduction of circ-RNF111 suppressed PNI in a SACC xenograft model. Circ-RNF111 regulated HMGB2 expression through targeted modulation of miR-361-5p. Taken together, circ-RNF111 stimulates PNI in SACC by miR-361-5p/HMGB2 axis and may serve as a potential therapeutic target for SACC.

Malignant primary tumor in left atrium with mitral valve invasion, pulmonary veins and cerebral metastasis: A case report

Malignant primary tumor in left atrium with mitral valve invasion, pulmonary veins and cerebral metastasis: A case report

Survival outcomes of laparoscopic versus open radical hysterectomy in early cervical cancer with incidentally identified high-risk factors

ObjectivePreviously, we suggested that patients with cervical cancer (CC) with tumors ≤2 cm on preoperative magnetic resonance imaging (MRI) are safe candidates for laparoscopic radical hysterectomy (LRH). Here, we aim to investigate whether LRH deteriorates the prognosis of patients with incidentally identified high-risk factors; lymph node metastasis (LNM) or parametrial invasion (PMI). MethodsWe identified patients with 2009 FIGO stage IB1 CC who underwent Type C LRH or open radical hysterectomy (ORH) at three tertiary hospitals between 2000 and 2019. Those with a tumor ≤2 cm on preoperative MRI who were not suspicious of LNM or PMI preoperatively were included, while those who were indicated to receive adjuvant treatment but did not actually receive it were excluded. Survival outcomes were compared between the LRH and ORH groups in the overall population, then narrowed down to those with LNM, and then to those with PMI. ResultsIn total, 498 patients were included: 299 in the LRH group and 199 in the ORH group. The LRH and ORH groups showed similar 3-year progression-free survival (PFS) (94.0% vs. 93.6%; P = 0.615) and 5-year overall survival (OS) rates (97.2% vs. 96.8%; P = 0.439). On pathologic examination, 49 (9.8%) and 16 (3.2%) patients had LNM and PMI, respectively, and 10 (2.0%) had both. In the LNM subgroup, 5-year PFS rate was not significantly different between the LRH and ORH groups (73.2% vs. 91.7%; P = 0.169). In the PMI subgroup, no difference in PFS was observed between the two groups (P = 0.893). ConclusionsLRH might not deteriorate recurrence and mortality rates in CC patients with tumors ≤2 cm when adjuvant treatment is appropriately administered, even if pathologic LNM and PMI are incidentally identified.

Prognostic Effect of Liver Resection in Extended Cholecystectomy for T2 Gallbladder Cancer Revisited: A Retrospective Cohort Study With Propensity Score-matched Analysis.

This study aimed to evaluate the effect of liver resection on the prognosis of T2 gallbladder cancer (GBC). Although extended cholecystectomy [lymph node dissection (LND) + liver resection] is recommended for T2 GBC, recent studies have shown that liver resection does not improve survival outcomes relative to LND alone. Patients with pT2 GBC who underwent extended cholecystectomy as an initial procedure and did not reoperation after cholecystectomy at 3 tertiary referral hospitals between January 2010 and December 2020 were analyzed. Extended cholecystectomy was defined as either LND with liver resection (LND+L group) or LND only (LND group). We conducted 2:1 propensity score matching to compare the survival outcomes of the groups. Of the 197 patients enrolled, 100 patients from the LND+L group and 50 from the LND group were successfully matched. The LND+L group experienced greater estimated blood loss ( P <0.001) and a longer postoperative hospital stay ( P =0.047). There was no significant difference in the 5-year disease-free survival (DFS) of the 2 groups (82.7% vs 77.9%, respectively, P =0.376). A subgroup analysis showed that the 5-year DFS was similar in the 2 groups in both T substages (T2a: 77.8% vs 81.8%, respectively, P =0.988; T2b: 88.1% vs 71.5%, respectively, P =0.196). In a multivariable analysis, lymph node metastasis [hazard ratio (HR) 4.80, P =0.006] and perineural invasion (HR 2.61, P =0.047) were independent risk factors for DFS; liver resection was not a prognostic factor (HR 0.68, P =0.381). Extended cholecystectomy including LND without liver resection may be a reasonable treatment option for selected T2 GBC patients.

Hypoxic tumor-derived exosomal miR-21 induces cancer-associated fibroblast activation to promote head and neck squamous cell carcinoma metastasis

BackgroundBoth microRNA-21-5p (miR-21) and the tumor microenvironment, including hypoxia and cancer-associated fibroblasts (CAFs), play a vital role in head and neck squamous cell carcinoma (HNSCC), but whether there is an interaction and the specific regulatory mechanism between them in the process of metastasis is still unclear. In this study, we aimed to elucidate the connection and regulatory mechanism of miR-21, hypoxia, and CAFs in HNSCC metastasis. MethodsThe underlying mechanisms of hypoxia inducible factor 1 subunit alpha (HIF1α) regulating miR-21 transcription, promoting exosome secretion, CAFs activation, tumor invasion, and lymph node metastasis were determined through quantitative real-time PCR, immunoblotting, transwell, wound healing, immunofluorescence, ChIP, electron microscopy, nanoparticle tracking analysis, dual-luciferase reporter assay, co-culture model and xenografts experiments. ResultsMiR-21 promoted the invasion and metastasis of HNSCC in vitro and in vivo, whereas HIF1α knockdown inhibited these processes. HIF1α upregulated transcription of miR-21 and promoted the release of exosomes from HNSCC cells. Exosomes derived from hypoxic tumor cells were rich in miR-21, which induced NFs activation towards CAFs by targeting YOD1. Knockdown the expression level of miR-21 in CAFs prevented lymph node metastasis in HNSCC. ConclusionHypoxic tumor cell-derived exosomal miR-21 might be a therapeutic target to prevent or delay HNSCC invasion and metastasis.

Organic Electronic Platform for Real-Time Phenotypic Screening of Extracellular-Vesicle-Driven Breast Cancer Metastasis.

Tumor-derived extracellular vesicles (TEVs) induce the epithelial-to-mesenchymal transition (EMT) in nonmalignant cells to promote invasion and cancer metastasis, representing a novel therapeutic target in a field severely lacking in efficacious antimetastasis treatments. However, scalable technologies that allow continuous, multiparametric monitoring for identifying metastasis inhibitors are absent. Here, the development of a functional phenotypic screening platform based on organic electrochemical transistors (OECTs) for real-time, noninvasive monitoring of TEV-induced EMT and screening of antimetastatic drugs is reported. TEVs derived from the triple-negative breast cancer cell line MDA-MB-231 induce EMT in nonmalignant breast epithelial cells (MCF10A) over a nine-day period, recapitulating a model of invasive ductal carcinoma metastasis. Immunoblot analysis and immunofluorescence imaging confirm the EMT status of TEV-treated cells, while dual optical and electrical readouts of cell phenotype are obtained using OECTs. Further, heparin, a competitive inhibitor of cell surface receptors, is identified as an effective blocker of TEV-induced EMT. Together, these results demonstrate the utility of the platform for TEV-targeted drug discovery, allowing for facile modeling of the transient drug response using electrical measurements, and provide proof of concept that inhibitors of TEV function have potential as antimetastatic drug candidates.

Tumor Infiltrating Lymphocytes (TILs) and Tumor Budding in Invasive Breast Carcinoma: Correlation with Known Prognostic Parameters

Background: Invasive breast cancer (IBC) has long been thought as non-immunogenic, but in recent decades it has been reported that tumour micro-environment (TME) in breast cancer encompasses tumor-infiltrating lymphocytes (TILs), which help in creating anti-tumor immune response. On the other hand, tumor buddings (TB) from the invasive front of the tumor contribute to invasion and metastasis. We aim to evaluate TILs and TB in IBC and to correlate them with known prognostic parameters. Methods: In this retrospective study, 50 cases of IBC were included. TILs and TB were observed and graded in H&amp;E Stained slides following standard guidelines. Associations of TILs and TB with known clinicopathological parameters were established by statistical methods. Results: The majority of cases were invasive breast carcinoma (IBC)-NST (78%). The cases with low TILs (involving &lt;50% of stroma) had a significant correlation with positive lymph node metastasis (P = 0.017) and high-grade TB (P = 0.038). TB was associated with other adverse prognostic parameters such as tumor necrosis (P=0.043) and lympho-vascular invasion (LVI) (P=0.033) and large tumor size. Conclusion: As tumor budding is associated with known poor prognostic factors such as necrosis, LVI and large tumor size, it can be regarded as a potential biomarker in predicting the aggressiveness of breast cancer. Low TILs are positively associated with invasion and lymph node metastasis of IBC. Thus, assessment of these protumor (TB) and antitumor (TILs) factors could be a promising approach for future research on breast cancer.

Role of creatine shuttle in colorectal cancer cells.

The creatine shuttle translocates the energy generated by oxidative phosphorylation to the cytoplasm via mitochondrial creatine kinase (MTCK) and creatine kinase B (CKB) in the cytoplasm. It is not apparent how the creatine shuttle is related to cancer. Here, we analyzed the expression and function of CKB and MTCK in colorectal cancer (CRC) and investigated the role of the creatine shuttle in CRC. Compared with normal mucosa, 184 CRC tissues had higher levels of CKB and MTCK, and these levels were associated with histological grade, tumor invasion, and distant metastasis. CK inhibitor dinitrofluorobenzene (DNFB) on CRC cell lines HT29 and CT26 inhibited cell proliferation and stemness to less than 2/3 and 1/20 of their control levels, respectively. In this treatment, the production of reactive oxygen species increased, mitochondrial respiration decreased, and mitochondrial volume and membrane potential decreased. In a syngeneic BALB/c mouse model using CT26 cells pretreated with DNFB, peritoneal metastasis was suppressed to 70%. Phosphorylation of EGFR, AKT, and ERK1/2 was inhibited in DNFB-treated tumors. High ATP concentrations prevented EGFR phosphorylation in HT29 cells following DNFB treatment, CKB or MTCK knockdown, and cyclocreatine administration. Despite not being immunoprecipitated, CKB and EGFR were brought closer together by EGF stimulation. These findings imply that blocking the creatine shuttle decreases the energy supply, suppresses oxidative phosphorylation, and blocks ATP delivery to phosphorylation signals, preventing signal transduction. These findings highlight the critical role of the creatine shuttle in cancer cells and suggest a potential new cancer treatment target.

RETRACTED ARTICLE: IL-1RA inhibits esophageal carcinogenesis and lymphangiogenesis via downregulating VEGF-C and MMP9

Interleukin-1 receptor antagonist (IL-1RA) has been shown to play an important role in cancer progression. However, its pathogenic effects and molecular mechanism in the malignant progression of esophageal squamous cell carcinoma (ESCC) remain largely unknown. This study was designed to explore the function of IL-1RA in ESCC and determine the relationship between IL-1RA and lymph node metastasis in ESCC patients. The clinical relevance of IL-1RA in relation to the clinicopathological features and prognosis of 100 ESCC patients was analyzed. The function and underlying mechanisms of IL-1RA in the growth, invasion, and lymphatic metastasis in ESCC were explored both in vitro and in vivo. The therapeutic effect of anakinra, an IL-1 receptor antagonist, on ESCC was also evaluated in animal experiments. Downregulation of IL-1RA was observed in ESCC tissues and cells and was found to be strongly correlated with pathological stage (P = 0.034) and lymphatic metastasis (P = 0.038). Functional assays demonstrated that upregulation of IL-1RA reduced cell proliferation, migration, and lymphangiogenesis both in vitro and in vivo. Mechanistic studies revealed that overexpression of IL-1RA activated the epithelial-to-mesenchymal transition (EMT) in the ESCC cells through activation of MMP9 and regulation of the expression and secretion of VEGF-C through the PI3K/NF-κB pathway. Anakinra treatment resulted in significant inhibition of tumor growth, lymphangiogenesis, and metastasis. IL-1RA inhibits lymph node metastasis of ESCC by regulating the EMT through activation of matrix metalloproteinase 9(MMP9) and lymphangiogenesis, driven by VEGF-C and the NF-κB signaling pathway. Anakinra may be an effective drug for the inhibition of ESCC tumor formation and lymph node metastasis.

Different Subtypes of Osteosarcoma: Histopathological Patterns and Clinical Behaviour

Osteosarcoma (OS) is a primary malignant bone tumour that usually occurs in children and adolescents. OS is a highly aggressive tumour type with a propensity for local invasion and systemic early metastasis to the lungs or other bones. According to the World Health Organization, there are different subtypes of OS, including conventional OS (osteoblastic, chondroblastic, fibroblastic), telangiectatic OS, low-grade OS, small-cell OS, parosteal OS, periosteal OS, and high-grade surface OS. In this mini review, we will discuss the background of OS and histopathological patterns and clinical behaviour of the disease. Understanding the subtypes of OS and their pathogenesis is crucial for developing more precise and effective therapies for OS patients.

Plasma lipid levels are associated with the CD8+ T-cell infiltration and prognosis of patients with pancreatic cancer.

Recently, researchers have found that the tumour microenvironment plays an important role in tumours. We aimed to investigate the effects of plasma lipids on the prognosis of patients with pancreatic cancer and the infiltration of CD8+ T lymphocytes in tumour tissue. We enrolled patients with pancreatic ductal adenocarcinoma (PDAC) who underwent pancreatic surgery between 2012 and 2021. Clinical pathological data were recorded; total cholesterol (TC) and triglyceride (TG) levels were measured; and tissue samples were collected. A tissue microarray was generated using collected tissue samples, and CD8 staining was performed to determine immunoreactive scores (IRSs). The correlations of TC and TG levels with clinicopathological characteristics and prognosis were analysed. Finally, the correlations of TC and TG levels with CD8+ T-cell infiltration were analysed. A total of 90 eligible PDAC patients were included. TC levels were significantly correlated with tumour grade and lymph node metastasis, and TG levels were significantly correlated with perineural invasion. The Kaplan-Meier survival analysis results indicated that the prognosis in the high TC group was significantly worse than that in the low TC group, and the prognosis in the high TG group was significantly worse than that in the low TG group. Cox multivariate analysis indicated that TC was an independent indicator of poor prognosis of pancreatic cancer patients after surgery. Spearman correlation analysis indicated that there were significant negative correlations between CD8 IRS and TC and between CD8 IRS and TG. TC and TG levels are significantly related to the prognosis of pancreatic cancer patients. They may be associated with tumour progression to higher grades, lymph node metastasis and/or nerve invasion. More importantly, TC and TG may reduce CD8+ T lymphocyte infiltration into pancreatic cancer tissue, affecting antitumour immune functions and immunotherapy efficacy.

Pancreatic cancer-derived small extracellular vesical ezrin activates fibroblasts to exacerbate cancer metastasis through STAT3 and YAP-1 signaling pathways.

Cancer-associated fibroblasts (CAFs), a major component of the tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC), play an important role in tumorigenesis, metastasis, and chemoresistance. Tumor-derived small extracellular vesicles (sEVs), which mediate cell-to-cell communication between cancer cells and fibroblasts, are also critical for cancer progression and metastasis. However, it remains unclear how PDAC cell-derived sEVs activate fibroblasts, which contributes to tumor progression. Here, we report that ezrin (EZR) expression in PDAC cell-derived sEVs (sEV-EZR) can activate fibroblasts, resulting in increased migration ability and high expression of α-SMA, PDGFRB, and high production of extracellular matrix in fibroblasts. Reciprocally, sEV-EZR-activated fibroblasts enhanced PDAC cell proliferation, invasion, and metastasis to the liver in animal models. Conversely, fibroblasts treated with PDAC cell-derived sEVs with EZR knockdown resulted in the reduced metastatic ability of PDAC. Mechanistically, we demonstrated that PDAC cell-derived sEV-EZR increases the STAT3 and YAP-1 signaling pathways to induce fibroblast activation, and the activated fibroblasts promote PDAC cell proliferation, invasion, and liver metastasis. Inhibition of the STAT3 and YAP-1 signaling pathways by gene knockdown can abrogate sEV-EZR-induced effects. These findings suggest that targeting the interaction between PDAC cell-derived sEV-EZR and fibroblasts is a potential therapeutic strategy for PDAC.

Quinacrine inhibits cMET-mediated metastasis and angiogenesis in breast cancer stem cells.

A trans-membrane receptor tyrosine kinase, cMET, belonging to the MET proto-oncogene family, is responsible for cancer metastasis and angiogenesis. But not much is known about the role of cMET in growth and progression of cancer stem cells (CSCs). Earlier studies have shown that Quinacrine (QC), a bioactive agent, has anti-CSCs activity. Here, the role of QC in deregulation of cMET-mediated metastasis and angiogenesis has been systematically evaluated in vitro in highly metastatic breast CSCs (mBCSCs), ex vivo in patient-derived breast cancer stem cells (PDBCSCs) and in vivo in xenograft mice model systems. Cell proliferation, migration, invasion and representative metastasis markers were upregulated in cMET-overexpressed cells and QC exposure inhibited these processes in both mBCSCs and PDBCSCs. Interestingly, metastasis was significantly inhibited by QC in cMET-overexpressed cells but comparatively lesser significant alteration of the process was noted in cMET-silenced cells. Increase in vascularization (in in ovo CAM assay), and cell-cell tube formation (in HUVECs), and enhanced MMP9 and MMP2 enzymatic activities (in gelatin zymography) were noted after cMET overexpression but these processes got reversed after cMET knockdown or QC treatment in cMET-overexpressed cells. QC inhibited angiogenesis significantly in cMET-overexpressed cells, but lesser significant change was observed in cMET-silenced cells. Reduction in tumor volume and decreased expression of metastatic and angiogenic markers were also noted in xenograft mice after QC treatment. Furthermore, QC inhibited cMET activity by dephosphorylation of its tyrosine residues (Y1234 and Y1356) and downregulation of its downstream cascade. Thus, QC inhibited the cMET-mediated metastasis and angiogenesis in in vitro, in ovo, in vivo and ex vivo model systems. Ligand (HGF) binding leads to receptor dimerization and phosphorylation of tyrosine kinase domain of cMET. This activates the cMET signaling cascade. The representative downstream metastasis and angiogenesis-related proteins get upregulated and induce the metastasis and angiogenesis process. But after the QC treatment, cMET get dephosphorylated and inactivated. As a result, the downstream signaling proteins of cMET along with the other representative metastatic and angiogenic factors get downregulated. These lead to inhibition of cMET-mediated metastasis and angiogenesis. (Created with BioRender.com).