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High circulating vitamin D levels and supplementation may lower prostate cancer mortality. To probe for direct effects of vitamin D signaling in the primary tumor, we assessed how activation of intratumoral vitamin D signaling in prostate cancer is associated with lethal prostate cancer during long-term follow-up. Among 404 participants with primary prostate cancer in the Health Professionals Follow-up Study and the Physicians' Health Study, we defined a gene score of expected activated intratumoral vitamin D signaling consisting of transcriptionally upregulated (CYP27A1 , CYP2R1 , RXRA , RXRB , and VDR) and downregulated genes (CYP24A1 and DHCR7). We contrasted vitamin D signaling in tumors that progressed to lethal disease (metastases/prostate cancer-specific death, n  = 119) over up to three decades of follow-up with indolent tumors that remained nonmetastatic for >8 years post-diagnosis (n  = 285). The gene score was downregulated in tumor tissue compared with tumor-adjacent histologically normal tissue of the same men. Higher vitamin D gene scores were inversely associated with lethal prostate cancer (odds ratio for highest versus lowest quartile: 0.46, 95% confidence interval: 0.21–0.99) in a dose–response fashion and after adjusting for clinical and pathologic factors. This association appeared strongest among men with high predicted plasma 25-hydroxyvitamin D3 and men with body mass index ≥25 kg/m2. Findings were replicated with broader gene sets. These data support the hypothesis that active intratumoral vitamin D signaling is associated with better prostate cancer outcomes and provide further rationale for testing how vitamin D-related interventions after diagnosis could improve prostate cancer survival through effects on the tumor. [ABSTRACT FROM AUTHOR]

Metastasis is the leading cause of cancer-related mortality; however, a complete understanding of the molecular programs driving the metastatic cascade is lacking. Metastasis is dependent on collective invasion—a developmental process exploited by many epithelial cancers to establish secondary tumours and promote widespread disease. The key drivers of collective invasion are "Leader Cells", a functionally distinct subpopulation of cells that direct migration, cellular contractility, and lead trailing or follower cells. While a significant body of research has focused on leader cell biology in the traditional context of collective invasion, the influence of metastasis-promoting leader cells is an emerging area of study. This review provides insights into the expanded role of leader cells, detailing emerging evidence on the hybrid epithelial–mesenchymal transition (EMT) state and the phenotypical plasticity exhibited by leader cells. Additionally, we explore the role of leader cells in chemotherapeutic resistance and immune evasion, highlighting their potential as effective and diverse targets for novel cancer therapies. [ABSTRACT FROM AUTHOR]

Background: β-1,3-Galactosyltransferase-4 (B3GALT4), a member of the β-1,3-galactosyltransferase gene family, is essential to the development of many malignancies. However, its biological function in breast cancer is still unknown. Method: Publically accessible datasets, as well as quantitative real-time PCR, western blot, and immunohistochemistry on our patient cohort were used to investigate the expression levels of B3GALT4 in breast cancer. The correlation of B3GALT4 expression with clinical histopathological data and mortality in breast cancer patients was investigated. The effects of B3GALT4 in breast cancer in vitro and in vivo were investigated. RNA-seq, western blot, autophagolysosomes, and the fluorescence intensity of LC3 were used to explore the effects of B3GALT4 on autophagy. Western blot and gene set enrichment analysis (GSEA) were used to identify the AKT/mTOR pathway. Results: B3GALT4 was significantly overexpressed in breast cancer tissues and was positively correlated with some aspects of clinicopathological status and poor prognosis. B3GALT4 overexpression significantly promoted cell proliferation, migration, and invasion, both in vitro and in vivo. B3GALT4 inhibition suppressed breast cancer cell proliferation, migration, and invasion in vitro. Suppression of B3GALT4 triggered autophagy and hindered the AKT/mTOR signaling pathway. Conclusion: According to the present research, B3GALT4 blocked autophagy via the AKT/mTOR pathway and accelerated the growth of breast cancer. B3GALT4 may be an effective target for patients with breast cancer. [ABSTRACT FROM AUTHOR]

Despite remarkable advances in immunotherapy, melanoma remains a significant cause of cancer mortality. Many factors concerning melanoma mortality are poorly understood, posing an obstacle to optimal care. We conducted a retrospective observational cohort study of 183 patients with metastatic melanoma who died following immunotherapy treatment to investigate sites of metastases at death, settings of death, and mechanisms of death. The median time from metastatic diagnosis to death was 16.1 months (range 0.3–135.1 months). Most patients experienced hospitalization within 3 months before death (80.3%), with 31.7% dying while hospitalized, 31.2% while in inpatient hospice, and 29.4% while in home hospice. The most common sites of metastases at death were distant lymph nodes (62.8%), lung (57.9%), liver (50.8%), brain (38.8%), and bone (37.7%). The most common causes of death were progressive failure to thrive (57.5%), respiratory failure (22.4%), and infection (21.8%); the vast majority (87.9%) of patients died from melanoma‐specific causes. Overall, 10.9% of patients in our cohort had survival >5 years after metastatic diagnosis, and 76.2% of long‐term survivors died due to melanoma. This study describes factors associated with melanoma mortality, highlighting an ongoing need for therapeutic advancements. [ABSTRACT FROM AUTHOR]

Metastasis leads to high mortality among cancer patients. It is a complex, multi-step biological process that involves the dissemination of cancer cells from the primary tumor and their systemic spread throughout the body, primarily through the epithelial-mesenchymal transition (EMT) program and immune evasion mechanisms. It presents a challenge in how to comprehensively treat metastatic cancer cells throughout the entire stage of the metastatic cascade using a simple system. Here, we fabricate a nanogel (HNO-NG) by covalently crosslinking a macromolecular nitric oxide (NO) donor with a photothermal IR780 iodide-containing hyaluronic acid derivative via a click reaction. This enables stable storage and tumor-targeted, photothermia-triggered release of NO to combat tumor metastasis throughout all stages. Upon laser irradiation (HNO-NG+L), the surge in NO production within tumor cells impairs the NF-κB/Snail/RKIP signaling loop that promotes the EMT program through S-nitrosylation, thus inhibiting cell dissemination from the primary tumor. On the other hand, it induces immunogenic cell death (ICD) and thereby augments anti-tumor immunity, which is crucial for killing both the primary tumor and systemically distributed tumor cells. Therefore, HNO-NG+L, by fully leveraging EMT reversal, ICD induction, and the lethal effect of NO, achieved impressive eradication of the primary tumor and significant prevention of lung metastasis in a mouse model of orthotropic 4T1 breast tumor that spontaneously metastasizes to the lungs, extending the NO-based therapeutic approach against tumor metastasis. [Display omitted] • Nanogel containing macromolecular NO donor enables double guarantee of NO storage. • HNO-NG + L with photothermia effect mediates spatiotemporal regulation of NO release under reducing conditions. • HNO-NG + L reverses EMT program, inhibiting cell dissemination from the primary tumor. • HNO-NG + L induces ICD, restoring systemic immune surveillance against tumor metastasis. [ABSTRACT FROM AUTHOR]

Colorectal cancer is one of the most common causes of cancer mortality worldwide, and innovative drugs for the treatment of colorectal cancer are continually being developed. 5-Fluorouracil (5-FU) is a common clinical chemotherapeutic drug. Acquired resistance to 5-FU is a clinical challenge in colorectal cancer treatment. Parecoxib is a selective COX-2-specific inhibitor that was demonstrated to inhibit metastasis in colorectal cancers in our previous study. This study aimed to investigate the synergistic antimetastatic activities of parecoxib to 5-FU in human colorectal cancer cells and determine the underlying mechanisms. Parecoxib and 5-FU synergistically suppressed metastasis in colorectal cancer cells. Treatment with the parecoxib/5-FU combination induced an increase in E-cadherin and decrease in β-catenin expression. The parecoxib/5-FU combination inhibited MMP-9 activity, and the NF-κB pathway was suppressed as well. Mechanistic analysis denoted that the parecoxib/5-FU combination hindered the essential molecules of the PI3K/Akt route to obstruct metastatic colorectal cancer. Furthermore, the parecoxib/5-FU combination could inhibit reactive oxygen species. Our work showed the antimetastatic capacity of the parecoxib/5-FU combination for treating colorectal cancers via the targeting of the PI3K/Akt/NF-κB pathway. [ABSTRACT FROM AUTHOR]

Gastric cancer (GC) with peritoneal carcinomatosis (PC) has a particularly unfavorable prognosis. This limited survival raises doubts about which factors confer an extremely worse outcome and which patients could benefit from more aggressive treatments, in an attempt to improve survival and better control the disease. This study aimed to evaluate the survival outcomes of patients with PC due to GC and develop a prognostic score to predict 6-month mortality. We performed an analysis of clinical stage IV GC with PC. Scores were assigned to risk factors and calculated for each patient from nine variables. Among 326 IVB GC, 211 (64.7%) had PC and were included. After calculating the score, 136 (64.5%) GCs were classified as a low-risk group and 75 (35.5%) as a high-risk group. Median OS was 7.9 and 1.9 months for low- and high-risk patients (p < 0.001). In the high-risk group, 77.3% of the patients died in <6 mo (p < 0.001). Palliative surgery and chemotherapy were associated with better survival, and the prognostic groups maintained statistical significance even when the same type of treatment was performed. In conclusion, the scoring system developed with variables related to patient performance status and clinical data was able to distinguish GC with PC with a high risk of 6-month mortality. Accordingly, verifying and validating our findings in a large cohort of patients is necessary to confirm and guarantee the external validation of the results. [ABSTRACT FROM AUTHOR]

Castration resistant prostate cancer (CRPC) is a challenging subset of prostate cancer associated with an extensive metastatic profile and high mortality. Ketoconazole is a nonselective steroid 17 a-hydroxylase/17,20 lyase (CYP17A1) inhibitor and is employed as a second line treatment option for CRPC with an established efficacy profile in patients. The aim of this study is to assess the efficacy of ketoconazole containing regimens for CRPC in terms of prostate specific antigen (PSA) decline rate using a systematic review and meta-analysis. In this review, an electronic search was carried out on PubMed, Cochrane CENTRAL, Scopus, and Google Scholar to find relevant literature. Random effects model was used to assess pooled PSA decline rate and 95% CIs. Publication bias was assessed using the funnel plot symmetry and one-tailed Egger's and Begg's test. In all cases, P -value < .05 was indicative of significant results. The review is registered with PROSPERO: CRD42023466536. A total of 483 articles were retrieved after database searching, out of which 23 studies (having a total of 1315 patients) were included in the review based on prespecified cr iter ia. The PSA decline rate was reported in the 14 observational studies (having 964 patients) and 9 experimental studies (having 351 patients). Pooled results revealed that 48.6% (95% CI 43.1-54.2; P -value < .001; I2 = 73.24%) of participants achieved more than 50% decline in PSA (602/1315 participants). Sensitivity analysis using the leave-one-out method revealed no substantial change in pooled effect estimates; (Risk Ratio) RR 47.2% to RR 49.8% demonstrating the robustness of our results. There was no evidence of publication bias as assessed from the funnel plot symmetry. Ketoconazole containing regimens have shown moderate efficacy in high risk CRPC patients as demonstrated by the pooled results. Hence, a ketoconazole based chemotherapy can be added to patients' regimen if there is a persistent rise in PSA levels after androgen deprivation therapy. [ABSTRACT FROM AUTHOR]

In clear-cell metastatic renal cell carcinoma (ccmRCC) patients, intensified treatment (systemic therapy [ST] + cytoreductive nephrectomy [CN]) does not result in higher other-cause mortality (OCM), than when ST is used alone. Conversely, a strong association with lower cancer-specific mortality was recorded in ST + CN patients, relative to their ST alone counterparts, even after strictest statistical adjustments. Background: The effect of treatment intensification (systemic therapy [ST] + cytoreductive nephrectomy (CN) vs. ST alone) is unknown regarding rates of other-cause mortality (OCM) in clear-cell metastatic renal cell carcinoma (ccmRCC). We hypothesized that intensified treatment (ST + CN) may result in higher OCM, than when ST is used alone. Methods: Within the Surveillance, Epidemiology, and End Results database, all ccmRCC patients treated 2010-2018 either with ST + CN or ST alone were identified. Propensity score matching (PSM), cumulative incidence plots, multivariable competing risks regression analyses and 6 months' landmark analyses addressed OCM and cancerspecific mortality (CSM) according to treatment status. Results: Of 2271 ccmRCC patients, 1233 (54%) were treated with ST + CN vs 1038 (46%) with ST alone. After 1:1 PSM, OCM was 5.3 vs. 4.6 % (P = .5) and CSM was 73.4 vs. 88.4% (P < .001) in ST + CN vs. ST alone patients. In multivariable competing risks regression, the combination of ST and CN was not associated with higher OCM (HR 1.3; 95% CI 0.8-2.1; P = .4), vs. ST alone. However, the combination of ST and CN was independently associated with lower CSM (HR 0.5; 95% CI 0.5-0.6; P < .001), vs. ST alone. After 6 months' landmark analyses, these multivariable associations remained unchanged. Conclusions: The current study indicates no OCM-disadvantage in ST + CN ccmRCC patients, relative to their ST alone counterparts. Conversely, a strong association with lower CSM was recorded in ST + CN patients, relative to their ST alone counterparts. These associations are robust and remained unchanged after strictest statistical adjustment including control for immortal time bias. [ABSTRACT FROM AUTHOR]

The leading cause of mortality in patients with breast cancer is metastasis, and bone morphogenetic protein (BMP) signaling activation regulates metastasis in breast cancer. This study explored the genetic and epigenetic modification of BMP receptor genes associated with metastatic breast cancer cells using bioinformatics. The genetic and epigenetic alterations of BMP receptors (BMPR1A, BMPR1B, BMPR2, ACVR2A, ACVR1, ACVR2B, ACVR1B, HJV, and ENG) were examined using cBioportal and methSurv, respectively. mRNA expression was analyzed using TNM plot and bcgenex, and protein expression was studied using Human Protein Atlas. Prognostic value and ROC were investigated using Kaplan–Meier (KM) and ROC plot, respectively. Finally, mutant function was predicted using several databases, including PolyPhen-2, FATHMM, Mutation Assessor, and PredictSNP. Oncoprint analysis showed genetic alterations in BMPR1A (39%), BMPR1B (13%), BMPR2 (34%), ACVR2A (14%), ACVR1 (7%), ACVR2B (13), ACVR1B (35%), HJV (40%), and ENG (33%) across the patients with breast cancer in The Metastatic Breast Cancer Project. The mRNA and protein levels of BMPR2 were increased in metastatic breast tumor tissues compared with those in normal and breast tumor tissues. BMPR1A and BMPR2 showed the highest and lowest levels of epigenetic alterations among the BMP receptors, respectively. The patients with breast cancer who had low levels of BMPR2 had a better overall survival (OS) than those with high levels of BMPR2. Functional mutation prediction showed that mutants in BMPR2 (R272L, E274K, and L685F), ACVR2A (S127L), and ACVR1B (R484H), are deleterious, probably damaging, and possess a cancer phenotype. ROC plot revealed no BMP receptors correlated with endocrine therapy sensitivity. BMPR1B, BMPR2, and ACVR2A levels were significantly linked as moderate prediction of anti-HER2, BMPR2, and ACVR1B demonstrated moderate predictive potential for chemotherapy sensitivity. This study contributed in fully comprehending the significance of genetic and epigenetic alterations in BMP receptors and BMP signaling in metastatic breast cancer cells for the development of breast cancer treatment plans. [ABSTRACT FROM AUTHOR]

Tumor metastasis involves complex processes that traditional 2D cultures and animal models struggle to fully replicate. Metastatic tumors undergo a multitude of transformations, including genetic diversification, adaptation to diverse microenvironments, and modified drug responses, contributing significantly to cancer-related mortality. Micro-physiological systems (MPS) technology emerges as a promising approach to emulate the metastatic process by integrating critical biochemical, biomechanical, and geometrical cues at a microscale. These systems are particularly advantageous simulating metastasis organotropism, the phenomenon where tumors exhibit a preference for metastasizing to particular organs. Organotropism is influenced by various factors, such as tumor cell characteristics, unique organ microenvironments, and organ-specific vascular conditions, all of which can be effectively examined using MPS. This review surveys the recent developments in MPS research from the past five years, with a specific focus on their applications in replicating tumor metastasis and organotropism. Furthermore, we discuss the current limitations in MPS-based studies of organotropism and propose strategies for more accurately replicating and analyzing the intricate aspects of organ-specific metastasis, which is pivotal in the development of targeted therapeutic approaches against metastatic cancers. [ABSTRACT FROM AUTHOR]

The incidence of distant metastases is associated with most cancer-related mortalities. Extracellular vesicles (EVs), secreted from tumors and cancer-associated fibroblasts, are involved in the metastatic process mediating their organotropism through their involvement in the pre-metastatic niche formation. We have been developing suicide gene therapy mediated by EVs secreted from mesenchymal stem/stromal cells, tumor cells, and cancer-associated fibroblasts. Suicide gene EVs conjugated with prodrug are tumor tropic, penetrate tumor cells, and kill them by intracellular conversion of nontoxic prodrug to an efficient anti-cancer drug. Here, we discuss findings regarding the possibility of using suicide gene EVs as a novel therapeutic approach for metastases, via pre-metastatic niche modification. The suicide gene EVs provide a future perspective for metastasis prevention. [ABSTRACT FROM AUTHOR]

Background: Lung cancer is a leading cause of cancer-related mortality worldwide, and effective therapies are limited. Lung cancer is a leading cause of cancer-related mortality worldwide with limited effective therapy. Sorafenib is a multi-tyrosine kinase inhibitor frequently used to treat numerous types of malignant tumors. However, it has been demonstrated that sorafenib showed moderate antitumor activity and is associated with several side effects in lung cancer, which restricted its clinical application. This study aimed to examine the antitumor effect of the combination treatment of sorafenib and 5-methoxytryptophan (5-MTP) on cell growth and metastasis of Lewis lung carcinoma (LLC) cells. Method: The anticancer effect of the combination treatment of sorafenib and 5-MTP was determined through cytotoxicity assay and colony forming assays. The mechanism was elucidated using flow cytometry and western blotting. Wound healing and Transwell assays were conducted to evaluate the impact of the combination treatment on migration and invasion abilities. An in vivo model was employed to analyze the effect of the combination treatment on the tumorigenic ability of LLC cells. Result: Our results demonstrated that the sorafenib and 5-MTP combination synergistically reduced viability and proliferation compared to sorafenib or 5-MTP treatment alone. Reduction of cyclin D1 expression was observed in the sorafenib alone or combination treatments, leading to cell cycle arrest. Furthermore, the sorafenib-5-MTP combination significantly increased the inhibitory effect on migration and invasion of LLC cells compared to the single treatments. The combination also significantly downregulated vimentin and MMP9 levels, contributing to the inhibition of metastasis. The reduction of phosphorylated Akt and STAT3 expression may further contribute to the inhibitory effect on proliferation and metastasis. In vivo, the sorafenib-5-MTP combination further reduced tumor growth and metastasis compared to the treatment of sorafenib alone. Conclusions: In conclusion, our data indicate that 5-MTP sensitizes the antitumor activity of sorafenib in LLC cells in vitro and in vivo, suggesting that sorafenib-5-MTP has the potential to serve as a therapeutic option for patients with lung cancer. [ABSTRACT FROM AUTHOR]

Background: Gallbladder cancer (GBC) remains a serious cause of cancer-related mortality across the globe. E2F5 has been identified to as a known oncogene in various cancers. However, the special functions of E2F5 have not been investigated in GBC. Aims: To explore the regulatory functions of E2F5 and its related molecular regulatory mechanism in GBC progression. Methods: The expression of genes were examined through qRT-PCR, western blot and IHC assay. The cell proliferation was assessed through CCK-8 and EDU assays. The cytotoxicity was tested through LDH assay. The percentage of CD8+ T cells and cell apoptosis were evaluated through flow cytometry. The binding ability was detected through luciferase reporter assay. The tumor growth was assessed through in vivo assays. Results: In this study, it was demonstrated that E2F5 expression was evaluated in GBC, and resulted into poor prognosis. Bioinformatics analysis revealed E2F5 as a target for let-7d-5p, which when overexpressed, suppressed the metastasis and proliferation of GBC through the downregulation of E2F5. It was discovered that E2F5 activates JAK2/STAT3 signaling which is suppressed by let-7d-5p, implicating this pathway as one of the effectors of the oncogenic effects of ESF5 in GBC. E2F5 had been confirmed to aggravate tumor growth in vivo. Conclusion: E2F5 targeted by let-7d-5p facilitated cell proliferation, metastasis and immune escape in GBC through the JAK2/STAT3 pathway. [ABSTRACT FROM AUTHOR]

Tumor metastasis is a significant contributor to the mortality of cancer patients. Specifically, current conventional treatments are unable to achieve complete remission of brain metastasis. This is due to the unique pathological environment of brain metastasis, which differs significantly from peripheral metastasis. Brain metastasis is characterized by high tumor mutation rates and a complex microenvironment with immunosuppression. Additionally, the presence of blood-brain barrier (BBB)/blood tumor barrier (BTB) restricts drug leakage into the brain. Therefore, it is crucial to take account of the specific characteristics of brain metastasis when developing new therapeutic strategies. Nanomaterials offer promising opportunities for targeted therapies in treating brain metastasis. They can be tailored and customized based on specific pathological features and incorporate various treatment approaches, which makes them advantageous in advancing therapeutic strategies for brain metastasis. This review provides an overview of current clinical treatment options for patients with brain metastasis. It also explores the roles and changes that different cells within the complex microenvironment play during tumor spread. Furthermore, it highlights the use of nanomaterials in current brain treatment approaches. [Display omitted] • The unique pathological environment of brain metastases limits clinical outcomes. • Different cell types play different roles and change during the progression of BM. • NMs can be customized to specific pathological features and thus offer significant advantages in BM treatment. [ABSTRACT FROM AUTHOR]

The metastasis of melanoma cells to regional lymph nodes and distant sites is an important contributor to cancer-related morbidity and mortality among patients with melanoma. This intricate process entails dynamic interactions involving tumor cells, cellular constituents, and non-cellular elements within the microenvironment. Moreover, both microenvironmental and systemic factors regulate the metastatic progression. Central to immunosurveillance for tumor cells are natural killer (NK) cells, prominent effectors of the innate immune system with potent antitumor and antimetastatic capabilities. Recognizing their pivotal role, contemporary immunotherapeutic strategies are actively integrating NK cells to combat metastatic tumors. Thus, a meticulous exploration of the interplay between metastatic melanoma and NK cells along the metastatic cascade is important. Given the critical involvement of NK cells within the melanoma tumor microenvironment, this comprehensive review illuminates the intricate relationship between components of the melanoma tumor microenvironment and NK cells, delineating their multifaceted roles. By shedding light on these critical aspects, this review advocates for a deeper understanding of NK cell dynamics within the melanoma context, driving forward transformative strategies to combat this cancer. [ABSTRACT FROM AUTHOR]

Metastasis is the leading cause of mortality in cancer patients. L-type amino acid transporter 1 (LAT1, SLC7A5) is a Na+-independent neutral amino acid transporter highly expressed in various cancers to support their growth. Although high LAT1 expression is closely associated with cancer metastasis, its role in this process remains unclear. This study aimed to investigate the effect of LAT1 inhibition on cancer metastasis using B16-F10 melanoma mouse models. Our results demonstrated that nanvuranlat (JPH203), a high-affinity LAT1-selective inhibitor, suppressed B16-F10 cell proliferation, migration, and invasion. Similarly, LAT1 knockdown reduced cell proliferation, migration, and invasion. LAT1 inhibitors and LAT1 knockdown diminished B16-F10 lung metastasis in a lung metastasis model. Furthermore, nanvuranlat and LAT1 knockdown suppressed lung, spleen, and lymph node metastasis in an orthotopic metastasis model. We discovered that the LAT1 inhibitor reduced the cell surface expression of integrin αvβ3. Our findings revealed that the downregulation of the mTOR signaling pathway, induced by LAT1 inhibitors, decreased the expression of integrin αvβ3, contributing to the suppression of metastasis. These results highlight the critical role of LAT1 in cancer metastasis and suggest that LAT1 inhibition may serve as a potential target for anti-metastasis cancer therapy. [ABSTRACT FROM AUTHOR]

Globally, lung cancer is a main cause of cancer-related mortality and morbidity related to cancer. Unfortunately, most cases are not detected and treated until the late stages of disease progression, and 50% of the patients present with established distant metastases. Common locations of distant metastases include the brain, bones, adrenal glands, and liver. However, metastasis to soft tissue, including skeletal muscles, is rare. In this case, we reported a rare presentation of gluteal muscle metastasis as the first complaint of primary adenocarcinoma of the lung in a 79-year-old man. Ultrasound revealed a right gluteal mass that raised the suspicion of an underlying occult malignancy. A histopathological evaluation also showed poorly differentiated adenocarcinoma (Immunophenotype: CK7+/TTF-1+/CK20-), favoring primary lung origin. Although soft tissue metastasis is a relatively rare site of distant spread, our case report underscores the need for a higher clinical sense and a lower threshold for biopsy, as these lesions might indicate an underlying hidden malignancy. [ABSTRACT FROM AUTHOR]

Background: Metastases are the leading cause of mortality in cancer patients. Linear and parallel are the two prominent models of metastatic progression. Metastases can be detected synchronously along with the primary tumor or metachronously, following treatment of localized disease. The aim of the study was to determine whether synchronous metastases (SM) and metachronous metastases (MM) differ only in lead-time or stem from different biological processes. Materials and methods: We retrospectively studied the chest CTs of 791 patients inflicted by eleven malignancy types that were treated in our institution in the years 2010–2020. Patient's population included 396 with SM and 395 with MM. The diameter of 15,427 lung metastases was measured. Clonal origin was deduced from the linear/parallel ratio (LPR)-a computerized analysis of metastases diameters. LPR of 1 suggests pure linear dissemination and − 1 pure parallel. Results: Patients with MM were significantly older (average of 62.9 vs 60.7 years, p = 0.02), and higher percentage of them were males (58.7% vs 51.1%, p = 0.03). Median overall survival of patients with MM and SM was remarkably similar (23 months and 26 months respectively, p = 0.774) when calculated from the time of metastases diagnosis. Parallel dissemination (LPR ≤ 0) was found in 35.4% of patients with MM compared to only 19.8% of the patients with SM (p < 0.00001). Conclusion: Patients with SM and MM differ in demography and in clonal origin. Different therapeutic approaches may be considered in these two conditions. [ABSTRACT FROM AUTHOR]

Introduction: Lung adenocarcinoma is a common cause of mortality in patients with cancer. Recent studies have indicated that copper-related cell death may not occur in the same way as previously described. Long non-coding RNAs (lncRNAs) play a key role in the occurrence and development of tumors; however, the relationship between cuproptosis and lncRNAs in tumorigenesis and lung adenocarcinoma (LUAD) treatment has not been well established. Our study aimed to construct a model to analyze the prognosis of lung adenocarcinoma in patients using a carcinogenesisrelated lncRNA (CR) signature. Methods: The transcriptional profiles of 507 samples from The Cancer Genome Atlas were assessed. Cox regression and co-expression analyses, and the least absolute shrinkage and selection operator (LASSO) were used to filter the CR and develop the model. The expression status of the six prognostic CRs was used to classify all samples into high- and low-risk groups. The overall disease-free survival rate was compared between the two groups. The Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes were used to identify the pathways and mechanisms involved in this model. Subsequently, immunotherapy response, sensitivity, and correlation analyses for several antitumor medications were performed. In vitro experiments, including qPCR, were conducted in nine lung adenocarcinoma cell lines and 16 pairs of lung adenocarcinoma and para-carcinoma tissues. Results: After confirmation using the ROC curve, patients in the low-risk category benefited from both overall and disease-free survival. Gene Ontology analysis highlighted cell movement in the model. In the in vitro experiments, qPCR results showed the expression levels of six CRs in 16 pairs of carcinoma and paracarcinoma tissues, which were in accordance with the results of the model. AL138778.1 is a protective factor that can weaken the invasion and migration of A549 cells, and AL360270.1 is a hazardous factor that promotes the invasion and migration of A549 cells. According to this model, targeted treatments such as axitinib, gefitinib, linsitinib, pazopanib, and sorafenib may be more appropriate for low-risk patients. Conclusion: Six CR profiles (AL360270.1, AL138778.1, CDKN2A-DT, AP003778.1, LINC02718, and AC034102.8) with predictive values may be used to evaluate the prognosis of patients with lung adenocarcinoma undergoing therapy. [ABSTRACT FROM AUTHOR]

The cancer is a serious health problem, which is The cancer death rate (cancer mortality) is 158.3 per 100,000 men and women per year (based on 2013–2017 deaths). Both clinical and translational studies have demonstrated that chronic inflammation is associated with Cancer progression. However, the precise mechanisms of inflammasome, and the pathways that mediate this phenomenon are not fully characterized. One of the most recently identified signaling pathways, whose activation seems to affect many metabolic disorders, is the "inflammasome" a multiprotein complex composed of NLRP3 (nucleotide-binding domain and leucine-rich repeat protein 3), ASC (apoptosis associated speck-like protein containing a CARD), and procaspase-1. NLRP3 inflammasome activation leads to the processing and secretion of the proinflammatory cytokines interleukin-1β (IL-1β) and IL-18. The goal of this paper is to review new insights on the effects of the NLRP3 inflammasome activation in the complex mechanisms of crosstalk between different organs, for a better understanding of the role of chronic inflammation in cancer pathogenesis. We will provide here a perspective on the current research on NLRP3 inflammasome, which may represent an innovative therapeutic target to reverse the malignancy condition consequences of the inflammation. AYM-qS3qtQKAqRzQ-vEXmk Video Abstract [ABSTRACT FROM AUTHOR]

Papillary thyroid cancer (PTC) is the most common subtype of differentiated thyroid cancer and shows an increase in incidence globally. However, follicular thyroid carcinoma shows a decreasing trend in incidence but has aggressive biological behavior. The study focused on the long-term outcomes of follicular thyroid carcinoma and features predictive of adverse outcomes. After reviewing the histology, 22 patients with follicular thyroid carcinoma and these patients were treated during the study period. The median period of follow-up was 132 months. Disease-free survival (DFS) at the end of the study period was 59%, and adverse outcomes were recorded at 36%. Evident or obscure distant metastasis at the time of diagnosis was the strong predictor of adverse outcomes, which included disease-specific mortality. The most typical site of distant metastases was the lungs. The osseous metastases did not respond fully, even when iodine avidity was retained. Follicular thyroid carcinoma is an aggressive subtype of differentiated thyroid carcinoma (DTC) and requires aggressive management. [ABSTRACT FROM AUTHOR]

Background: 3D culture is increasingly used in cancer research, as it allows the growth of cells in an environment that mimics in vivo conditions. Metastases are the primary cause of morbidity and mortality in cancer patients, and solid tumour metastases are mostly located in lymph nodes. Currently, there are no techniques that model the pre-metastatic lymph node microenvironment in vitro. In this study, we prepared a novel extracellular matrix, Lymphogel, which is derived from lymph nodes, mimicking the tumour microenvironment (TME) of metastatic carcinoma cells. We tested the suitability of the new matrix in various functional experiments and compared the results with those obtained using existing matrices. Methods: We used both commercial and patient-derived primary and metastatic oral tongue squamous cell carcinoma (OTSCC) cell lines. We characterized the functional differences of these cells using three different matrices (human uterine leiomyoma-derived Myogel, human pre-metastatic neck lymph node-derived Lymphogel (h-LG), porcine normal neck lymph node-derived Lymphogel (p-LG) in proliferation, adhesion, migration and invasion assays. We also performed proteomic analyses to compare the different matrices in relation to their functional properties. Results: OTSCC cells exhibited different adhesion and invasion patterns depending on the matrix. Metastatic cell lines showed improved ability to adhere to h-LG, but the effects of the matrices on cell invasion fluctuated non-significantly between the cell lines. Proteomic analyses showed that the protein composition between matrices was highly variable; Myogel contained 618, p-LG 1823 and h-LG 1520 different proteins. The comparison of all three matrices revealed only 120 common proteins. Analysis of cellular pathways and processes associated with proteomes of each matrix revealed similarities of Myogel with h-LG but less with p-LG. Similarly, p-LG contained the least adhesion-related proteins compared with Myogel and h-LG. The highest number of unique adhesion-related proteins was present in h-LG. Conclusions: We demonstrated that human pre-metastatic neck lymph node-derived matrix is suitable for studying metastatic OTSCC cells. As a whole-protein extract, h-LG provides new opportunities for in vitro carcinoma cell culture experiments. [ABSTRACT FROM AUTHOR]

Prostate cancer morbidity and mortality are increasing globally and in China, and the rate of metastasis is also rising, limiting the therapeutic effect and clinical prognosis of prostate cancer. CD151 is considered to be the first promoter of tumor metastasis in the tetraspanin superfamily. Previous research has linked CD151 to the progression of a number of malignancies, including prostate cancer. However, a recent study found that CD151 can inhibit the progression of prostate cancer. As a result, this paper examines existing research on CD151 and prostate cancer progression in order to clarify the relationship and provide a possible reference for future studies. [ABSTRACT FROM AUTHOR]

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Metastasis is the main cause of cancer-related mortality; therefore, the ability to predict its propensity can remarkably affect survival rate. Metastasis development is predicted nowadays by lymph-node status, tumor size, histopathology, and genetic testing. However, all these methods may have inaccuracies, and some require weeks to complete. Identifying novel prognostic markers will open an essential source for risk prediction, possibly guiding to elevated patient treatment by personalized strategies. Cancer cell invasion is a critical step in metastasis. The cytoskeletal mechanisms used by metastatic cells for the invasion process are very similar to the utilization of actin cytoskeleton in the endocytosis process. In the current study, the adhesion and encapsulation efficiency of low-cost carboxylate-modified fluorescent nanoparticles by breast cancer cells with high (HM) and low metastatic potential (LM) have been evaluated; benign cells were used as control. Using high-content fluorescence imaging and analysis, we have revealed (within a short time of 1 h), that efficiency of nanoparticles adherence and encapsulation is sufficiently higher in HM cells compared to LM cells, while benign cells are not encapsulating or adhering the particles during experiment time at all. We have utilized custom-made automatic image analysis algorithms to find quantitative co-localization (Pearson's coefficients) of the nanoparticles with the imaged cells. The method proposed here is straightforward; it does not require especial equipment or expensive materials nor complicated cell manipulations, it may be potentially applicable for various cells, including patient-derived cells. Effortless and quantitative determination of the metastatic likelihood has the potential to be performed using patient-specific biopsy/surgery sample, which will directly influence the choice of protocols for cancer patient's treatment and, as a result, increase their life expectancy. [ABSTRACT FROM AUTHOR]

Cancer metastasis is a crucial step of malignancy progression determined by cancer cell-intrinsic properties and extrinsic environmental factors. The intratumor microbiota is a novel cancer component that functionally impinges on tumor progression in broad cancer types. The intratumor microbiota is present in tumor tissue at low abundance and low diversity, with predominant intracellular localization. The intratumor microbiota is implicated in distinguishing normal versus cancer tissue, drug responder versus nonresponder cancer, good versus bad prognosis, and metastatic versus non-metastatic cancers. Modulation of the intratumor microbiota can reduce cancer metastasis, impede cancer progression, and reprogram the immune response. Cancer metastasis is the leading cause of mortality in patients with cancer. Theories have been developed to explain the causes and principles of metastasis. Metastasis is attributed to cancer cell-intrinsic properties and the extrinsic cellular environment. In recent years, the intratumor microbiota has been identified as an integral tumor component and may functionally regulate various aspects of metastasis. These novel discoveries in intratumor microbiota reshape the framework of our understanding of metastasis and reveal a new path for studies on cancer progression and clinical cancer management. Here, we summarize recent advances in the emerging roles of intratumor microbiota in cancer metastasis and discuss the challenges and implications for cancer treatment. [ABSTRACT FROM AUTHOR]

The spread of tumor cells and the formation of distant metastasis remain the main causes of mortality in cancer patients. However, the mechanisms governing the release of cells from micro-environmental constraints remain unclear. E-cadherin negatively controls the invasion of epithelial cells by maintaining cell–cell contacts. Furthermore, the inactivation of E-cadherin triggers invasion in vitro. However, the role of E-cadherin is complex, as metastasizing cells maintain E-cadherin expression, which appears to have a positive role in the survival of tumor cells. In this report, we present a novel mechanism delineating how E-cadherin function is modulated to promote invasion. We have previously shown that E-cadherin is associated with p100AmotL2, which is required for radial actin formation and the transmission of mechanical force. Here, we present evidence that p60AmotL2, which is expressed in invading tumor cells, binds to the p100AmotL2 isoform and uncouples the mechanical constraint of radial actin filaments. We show for the first time that the coupling of E-cadherin to the actin cytoskeleton via p100AmotL2 is directly connected to the nuclear membrane. The expression of p60AmotL2 inactivates this connection and alters the properties of the nuclear lamina, potentiating the invasion of cells into micropores of the extracellular matrix. In summary, we propose that the balance of the two AmotL2 isoforms is important in the modulation of E-cadherin function and that an imbalance of this axis promotes ameboid cell invasion. [ABSTRACT FROM AUTHOR]

Background: Cutaneous melanoma is a relentless form of cancer which continues to rise in incidence. Currently, cutaneous melanoma is the leading cause of skin cancer‐related mortality, which can mainly be attributed to its metastatic potential. The activation of chemokine axes is a major contributor to melanoma metastasis through its involvement in promoting tumour cell migration, proliferation, survival, and adhesion. This review will focus on the role of chemokines in melanoma and possible therapeutic strategies to alter chemokine activation and subsequently inhibit the activation of signalling cascades that may promote metastasis. Methods: A literature review was conducted to evaluate chemokines as possible therapeutic targets in metastatic melanoma. Results: The crosstalk between signalling pathways and immune responses in the melanoma microenvironment resembles a complex and dynamic system. Therefore, the involvement of governing chemokine axes in the promotion of cutaneous and metastatic melanoma demands a proper understanding of the tumour microenvironment in order to identify possible targets and develop appropriate treatments against melanoma. Conclusion: Even though chemokine axes are regarded as promising therapeutic targets, it has become increasingly evident that chemokines can play a critical role in both tumour inhibition and promotion. The inhibition of chemokine axes to inhibit signalling cascades in target cells that regulate metastasis should, therefore, be carefully approached. [ABSTRACT FROM AUTHOR]

Although previous studies have shed light on the etiology of cervical cancer, metastasis of advanced cervical cancer remains the main reason for the poor outcome and high cancer-related mortality rate. Cervical cancer cells closely communicate with immune cells recruited to the tumor microenvironment (TME), such as lymphocytes, tumor-associated macrophages, and myeloidderived suppressor cells. The crosstalk between tumors and immune cells has been clearly shown to foster metastatic dissemination. Therefore, unraveling the mechanisms of tumor metastasis is crucial to develop more effective therapies. In this review, we interpret several characteristics of the TME that promote the lymphatic metastasis of cervical cancer, such as immune suppression and premetastatic niche formation. Furthermore, we summarize the complex interactions between tumor cells and immune cells within the TME, as well as potential therapeutic strategies to target the TME. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is the third most prevalent cancer with the second-highest mortality rate worldwide. microRNAs (miRNAs) of cancer-derived exosomes have shown promising diagnosis potential. Recent studies have shown the metastatic potential of a specific group of microRNAs called metastasis. Therefore, down-regulation of miRNAs at the transcriptional level can reduce metastasis probability. The aim of this bioinformatics research is targeting of miRNAs precursors using CRISPR-C2c2 (Cas13a) technique. The C2c2 (Cas13a) enzyme structure was downloaded from the RCSB database, the sequence miRNAs and their precursors were collected from miRbase. The crRNAs were designed and evaluated for their specificity by using CRISPR-RT server. The modeling 3D structure of the designed crRNA was performed by RNAComposer server. Finally, HDOCK server was used to perform molecular docking to evaluate docked molecules' energy level and position. The crRNAs designed for miR-1280, miR-206, miR-195, miR-371a, miR-34a, miR-27a, miR-224, miR-99b, miR-877, miR-495 and miR-384 that showed high structural similarity with the situation observed in normal and appropriate orientation was obtained. Despite high specificity, the correct orientation was not established in the case of crRNAs that designed to target miR-145, miR-378a, miR-199a, miR320a and miR-543. The predicted interactions between crRNAs and Cas13a enzyme showed that crRNAs have a strong potential to inhibit metastasis. Therefore, crRNAs may be considered as an effective anticancer agent for further research in drug development. [ABSTRACT FROM AUTHOR]

Large-scale, contemporary, controlled analysis of mortality in metastatic collecting duct renal carcinoma are scarce. Moreover, the optimal management of these patients is unknown. Within the SEER, 155 metastatic collecting duct renal carcinoma patients were identified. Despite the aggressive behavior and dismal survival prognosis, combination of cytoreductive nephrectomy and systemic therapy provide the lowest mortality rates. Introduction: Controlled contemporary analyses of mortality in metastatic collecting duct renal cell carcinoma (mcdRCC) are unavailable. We addressed this knowledge gap and tested rates of treatment and associated mortality in patients with mcdRCC. Patients and Methods: Within Surveillance, Epidemiology, and End Results database (2004-2018), we identified 155 mcdRCC patients. Kaplan-Meier plots and Cox proportional hazards regression models tested the effect of treatment (cytoreductive nephrectomy [CN] alone vs. systemic therapy [ST] alone vs. combination of both CN + ST) on overall mortality (OM). Results: In the overall cohort (n = 155), 57 patients (37%) were treated with combination of both CN + ST, 46 (30%) underwent CN alone, 28 (18%) received ST alone, and 24 (15%) had none/unknown treatment. According to age categories (= 59 vs. 60-69 vs. = 70 years), rates of combination of both CN + ST were 45% vs. 45% vs. 14%, respectively. CN alone was the most frequent type of treatment in patients aged = 70 (50%). Median overall survival was 4.0 months for CN alone vs. 5.5 months for ST alone vs. 9.0 months for combination of both CN + ST. In multivariable Cox regression models, where CN alone was the referent, the use of ST alone and combination of both CN + ST were respectively associated with a HR of 0.74 (P = .3) and 0.43 (P < .001), after adjustment for all covariates. Conclusions: In mcdRCC patients, concomitant use of CN and ST results in lowest mortality, followed by ST alone, and CN alone. In consequence combination of both CN + ST should be recommended whenever applicable. [ABSTRACT FROM AUTHOR]

Background: Metastasis is the leading cause of mortality in patients with breast cancer (BC). Studies demonstrate that circular RNAs (circRNAs) were involved in BC progression, while the molecular mechanisms remain largely unclear. Methods: The microArray circRNA profiles were used to explore the differential expression circRNAs in BC and paracancerous normal tissues, and the quantitative reverse transcription-polymerase chain reaction was used to validate their expression level in clinical samples and cell lines. Nuclear/cytosolic fractionation and fluorescence in situ hybridization (FISH) assays were performed to examine circRRM2 (hsa_circ_0052582) subcellular location. The scratch wound healing and transwell assays were conducted to evaluate the impact of circRRM2 on BC cell migration and invasion. We predicted miRNAs that might bind with cricRRM2 and the downstream target genes using bioinformatics analysis and explored their expression levels and prognostic value in BC. FISH, RNA immunoprecipitation, Co-immunoprecipitation, Western blot, and rescue experiments were implemented to figure out circRRM2 function and underlying mechanisms in BC. Results: The present study revealed several aberrant circRNAs in BC tissues and observed that circRRM2 was upregulated in tumor tissues of 40 patients with BC. High circRRM2 was significantly associated with advanced N stage in patients with BC. Gain- and loss- of function experiments revealed that circRRM2 promoted the migration and invasion of cells and functioned as an oncogene in BC. Mechanism studies showed that circRRM2 competed with miR-31-5p/miR-27b-3p to upregulate the IGF2BP1 expression. Furthermore, IGF2BP1 upregulated the circRRM2 level via interacting with MYC, which functioned as the transcriptional factor of circRRM2. Thus, the positive feedback loop that was composed of circRRM2/IGF2BP1/MYC was identified. Conclusion: This study confirms that upregulated circRRM2 functions an oncogenic role in BC metastasis. The positive feedback loop of circRRM2/IGF2BP1/MYC enforces the circRRM2 expression, which might offer a potential target for BC treatment. [ABSTRACT FROM AUTHOR]

Breast cancer is the most common type of cancer diagnosed among women worldwide. It significantly contributes to cancer-related mortality in females. Early-stage breast cancers have a high cure rate. However, distant metastasis of breast cancer due to haematological and lymphatic spread often leads to a poor prognosis. Gastric and duodenal metastasises are rarely observed in invasive lobular carcinoma of the breast. Early diagnosis is challenging due to the non-specific symptoms, the limited specificity of radiological investigations and the difficulty in obtaining adequate tissue biopsy. Herein, we report the clinical, radiological, and macroscopic features of a 72-year-old female with rare gastric metastasis of breast cancer and likely concurrent duodenal metastasis. [ABSTRACT FROM AUTHOR]

Tumor spread is responsible for most deaths related to cancer. Increasing the accuracy of cancer prognosis is critical to reducing the high mortality rates in cancer patients. Here, we report that the electrostatic potential difference (EPD) between tumor and its paratumor tissue is a prognostic marker for tumor spread. This finding is concluded from the patient‐specific EPD values and clinical observation. The electrostatic potential values were measured on tissue cryosections from 51 patients using Kelvin probe force microscopy (KPFM). A total of ~44% (15/34) patients of Vtumor–paratumor > 0 were featured with tumor spread, whereas only ~18% (2/11) patients of Vtumor–paratumor < 0 had tumor spread. Next, we found the increased enrichment of cancer stem cells in paratumors with lower electrostatic potentials using immunofluorescence imaging, which suggested the attribution of tumor spread to the galvanotaxis of cancer stem cells (CSCs) toward lower potential. The findings were finally validated in breast and lung spheroid models composed of differentiated cancer cells and cancer stem cells at the ratio of 1:1 and embedded in Matrigel dopped with negative‐, neutral‐ and positive‐charged polymers and CSCs prefer to spread out of spheroids to lower electrostatic potential sites. This work may inspire the development of diagnostic and prognostic strategies targeting at tissue EPDs and CSCs for tumor therapy. [ABSTRACT FROM AUTHOR]

Background: Metastasis is the predominant cause of mortality in patients with breast cancer. Long noncoding RNAs (lncRNAs) have been shown to drive important phenotypes in tumors, including invasion and metastasis. However, the lncRNAs involved in metastasis and their molecular and cellular mechanisms are still largely unknown. Methods: The transcriptional and posttranscriptional processing of LINC00478-associated cytoplasmic RNA (LacRNA) was determined by RT-qPCR, semiquantitative PCR and 5′/3′ RACE. Paired-guide CRISPR/cas9 and CRISPR/dead-Cas9 systems was used to knock out or activate the expression of LacRNA. Cell migration and invasion assay was performed to confirm the phenotype of LacRNA. Tail vein model and mammary fat pad model were used for in vivo study. The LacRNA-PHB2-cMyc axis were screened and validated by RNA pulldown, mass spectrometry, RNA immunoprecipitation and RNA-seq assays. Results: Here, we identified a novel cytoplasmic lncRNA, LacRNA (LINC00478-associated cytoplasmic RNA), derived from nucleus-located lncRNA LINC00478. The nascent transcript of LINC00478 full-length (LINC00478_FL) was cleaved and polyadenylated, simultaneously yielding 5′ ends stable expressing LacRNA, which is released into the cytoplasm, and long 3′ ends of nuclear-retained lncRNA. LINC00478_3′RNA was rapidly degraded. LacRNA significantly inhibited breast cancer invasion and metastasis in vitro and in vivo. Mechanistically, LacRNA physically interacted with the PHB domain of PHB2 through its 61–140-nt region. This specific binding affected the formation of the autophagy degradation complex of PHB2 and LC3, delaying the degradation of the PHB2 protein. Unexpectedly, LacRNA specifically interacted with PHB2, recruited c-Myc and promoted c-Myc ubiquitination and degradation. The negatively regulation of Myc signaling ultimately inhibited breast cancer metastasis. Furthermore, LacRNA and LacRNA-mediated c-Myc signaling downregulation are significantly associated with good clinical outcomes, take advantage of these factors we constructed a prognostic predict model. Conclusion: Therefore, our findings propose LacRNA as a potential prognostic biomarker and a new therapeutic strategy. [ABSTRACT FROM AUTHOR]

Metastasis is the most prevalent cause of cancer deaths, and immunological components of the tumor microenvironment, especially tumor‐associated macrophages (TAMs), play a vital role in cancer metastasis. However, the underlying mechanisms of TAMs on non‐small‐cell lung cancer (NSCLC) metastasis remain largely unexplored. Herein, we demonstrated that M2‐like TAMs facilitate the migration and invasion of cancer cells in vitro and in vivo through intercellular delivery of M2‐like macrophage‐derived exosomes (M2‐exos). Importantly, we found that M2‐exos had considerably higher levels of integrin (ITG) αV and β3. The impact of M2‐like macrophage‐mediated invasion and migration of NSCLC cells was clearly decreased when ITG αVβ3 was blocked. Mechanistically, exosomal ITG αVβ3 produced from M2‐like macrophages successfully triggered the focal adhesion kinase signaling pathway in recipient cells, boosting the migratory and invasive abilities of NSCLC cells. Clinically, we found that metastatic NSCLC patients had greater ITG αV and β3 expression, which was associated with a worse prognosis. This study reveals a novel mechanism by which M2‐exos significantly increased NSCLC cell migration and invasion by delivering integrin αVβ3. Exosomal ITG αVβ3 can be used as a potential prognostic marker, and blocking ITG αVβ3 could be a viable treatment option for preventing tumor metastasis. [ABSTRACT FROM AUTHOR]

Background and Objectives: Colorectal cancer (CRC) is a leading cause of cancer-related mortality and morbidity worldwide. Bevacizumab was approved for the treatment of metastatic colorectal cancer (mCRC) based on favorable benefit-risk assessments from randomized controlled trials, but evidence on its use in the real-world setting is limited. The aim of the current study is to evaluate the outcomes and safety profile of bevacizumab in mCRC in a real-world setting in Romania. Patients and Methods: This was an observational, retrospective, multicentric, cohort study conducted in Romania that included patients with mCRC treated with bevacizumab as part of routine clinical practice. Study endpoints were progression-free survival, overall survival, adverse events, and patterns of bevacizumab use. Results: A total of 554 patients were included in the study between January 2008 and December 2018. A total of 392 patients (71%) received bevacizumab in the first line and 162 patients (29%) in the second line. Bevacizumab was mostly combined with a capecitabine/oxaliplatin chemotherapy regimen (31.6%). The median PFS for patients treated with bevacizumab was 8.4 months (interquartile range [IQR], 4.7–15.1 months) in the first line and 6.6 months (IQR, 3.8–12.3 months) in the second line. The median OS was 17.7 months (IQR, 9.3–30.6 months) in the first line and 13.5 months (IQR, 6.7–25.2 months) in the second line. Primary tumor resection was associated with a longer PFS and OS. The safety profile of bevacizumab combined with chemotherapy was similar to other observational studies in mCRC. Conclusions: The safety profile of bevacizumab was generally as expected. Although the PFS was generally similar to that reported in other studies, the OS was shorter, probably due to the less frequent use of bevacizumab after disease progression and the baseline patient characteristics. Patients with mCRC treated with bevacizumab who underwent resection of the primary tumor had a higher OS compared to patients with an unresected primary tumor. [ABSTRACT FROM AUTHOR]

Data on diet and survival among people with metastatic colorectal cancer are limited. We examined dietary fat in relation to all‐cause mortality and cancer progression or death among 1149 people in the Cancer and Leukemia Group B (Alliance)/Southwest Oncology Group (SWOG) 80405 trial who completed a food frequency questionnaire at initiation of treatment for advanced or metastatic colorectal cancer. We examined saturated, monounsaturated, total and specific types (n‐3, long‐chain n‐3 and n‐6) of polyunsaturated fat, animal and vegetable fats. We hypothesized higher vegetable fat intake would be associated with lower risk of all‐cause mortality and cancer progression. We used Cox proportional hazards regression to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI). Over median follow‐up of 6.1 years (interquartile range [IQR]: 5.3, 7.2 y), we observed 974 deaths and 1077 events of progression or death. Participants had a median age of 59 y; 41% were female and 86% identified as White. Moderate or higher vegetable fat was associated with lower risk of mortality and cancer progression or death (HRs comparing second, third and fourth to first quartile for all‐cause mortality: 0.74 [0.62, 0.90]; 0.75 [0.61, 0.91]; 0.79 [0.63, 1.00]; P trend:.12; for cancer progression or death: 0.74 [0.62, 0.89]; 0.78 [0.64, 0.95]; 0.71 [0.57, 0.88]; P trend:.01). No other fat type was associated with all‐cause mortality and cancer progression or death. Moderate or higher vegetable fat intake may be associated with lower risk of cancer progression or death among people with metastatic colorectal cancer. [ABSTRACT FROM AUTHOR]

Colorectal cancer represents a leading cause of cancer-related morbidity and mortality. Despite improvements, chemotherapy remains the backbone of colorectal cancer treatment. The aim of this study is to investigate the variation of circulating microRNA expression profiles and the response to irinotecan-based treatment in metastatic colorectal cancer and to identify relevant target genes and molecular functions. Serum samples from 95 metastatic colorectal cancer patients were analyzed. The microRNA expression was tested with a NucleoSpin miRNA kit (Machnery-Nagel, Germany), and a machine learning approach was subsequently applied for microRNA profiling. The top 10 upregulated microRNAs in the non-responders group were hsa-miR-181b-5p, hsa-miR-10b-5p, hsa-let-7f-5p, hsa-miR-181a-5p, hsa-miR-181d-5p, hsa-miR-301a-3p, hsa-miR-92a-3p, hsa-miR-155-5p, hsa-miR-30c-5p, and hsa-let-7i-5p. Similarly, the top 10 downregulated microRNAs were hsa-let-7d-5p, hsa-let-7c-5p, hsa-miR-215-5p, hsa-miR-143-3p, hsa-let-7a-5p, hsa-miR-10a-5p, hsa-miR-142-5p, hsa-miR-148a-3p, hsa-miR-122-5p, and hsa-miR-17-5p. The upregulation of microRNAs in the miR-181 family and the downregulation of those in the let-7 family appear to be mostly involved with non-responsiveness to irinotecan-based treatment. [ABSTRACT FROM AUTHOR]

Peritoneal carcinomatosis (PC) refers to metastatic spread of tumor into the peritoneal cavity. Earlier, PC was thought to be associated with grave clinical outcome. However, various advances in treatment options including cytoreductive surgery and heated intraperitoneal chemotherapy or early post-operative chemotherapy can prolong survival of patients with peritoneal carcinomatosis. These treatment options are associated with high morbidity and mortality. The purpose of this article is to acquaint the radiologist about various appearances of peritoneal carcinomatosis in order to help clinicians in selecting candidates for surgery and avoid unnecessary potentially debilitating surgeries in patients with unresectable PC. [ABSTRACT FROM AUTHOR]

Lung cancer is the leading cause of cancer-related mortality worldwide with an increasing incidence in many countries. There were few studies on arterial and venous thromboembolism (ATE/VTE) in patients with metastatic lung cancer. Our study focused on the clinical characteristics of stage IV lung cancer patients with ATE or VTE to further explore the risk factors and prognosis. Patients diagnosed with metastatic lung cancer were enrolled from January 2011 to June 2019 at a tertiary hospital in Jiangyin, China. Log-rank test was used to reveal the survival for patients with ATE or VTE. Univariable analysis and multivariable logistic regression were used to study the risk factors for ATE. A total of 587 patients were enrolled in our study, including 52 patients with VTE and 48 with ATE. ATE occurred earlier than VTE. Patients with ATE had a worse prognosis. Multivariable logistic regression revealed that older age and a history of hypertension were independent risk factors for ATE. Patients with metastatic lung cancer were at high risk of VTE and ATE. ATE occurred earlier and was associated with a worse prognosis. Attention should be paid to metastatic lung cancer patients who may develop thromboembolism, especially ATE. [ABSTRACT FROM AUTHOR]

Background: Cancer is a generic term for a large group of diseases that can affect any part of the body. One defining feature of cancer is the rapid creation of abnormal cells that grow beyond their usual boundaries, and which can then invade adjoining parts of the body and spread to other organs, the latter process is referred to as metastasizing. Metastases are a major cause of death from cancer. According to the World Health Organization, Cancer is the second leading cause of death globally, and was responsible for an estimated 9.6 million deaths in 2018. Globally, about 1 in 6 deaths is due to cancer. Approximately 70 percent of deaths from cancer occur in low- and middle-income countries. Around one third of deaths from cancer are due to the 5 leading behavioral and dietary risks: high body mass index, low fruit and vegetable intake, lack of physical activity, tobacco use, and alcohol use. About 28,082 people in Andhra Pradesh died of cancer in 2015, according to the Indian Council of Medical Research which finds that breast cancer is common among women followed by cervical cancer. Between 30-50 percent of cancers can currently be prevented by avoiding risk factors and implementing existing evidence-based prevention strategies. The cancer burden can also be reduced through early detection of cancer and management of patients who develop cancer. Many cancers have a high chance of cure if diagnosed early and treated adequately. Knowledge serves to be the fundamental key to curb this fatal disease. Objectives: The objectives of the present study were 1. To assess the knowledge on breast cancer among women in selected area, Visakhapatnam. 2. To determine the association between knowledge on breast cancer and selected demographic variables. Methods: A descriptive study was conducted in Sheelanagar, Visakhapatnam from March 2019 - April 2019 in women aged of 21 - 50 years. The sample size was one hundred (100) respondents chosen by convenient sampling technique. Data for the study was collected using self-designed structured questionnaire. Data collected and analyzed by using descriptive statistical methods. Chi square test was used to test association. Results: Results showed that 38 percent of the study population belonged to age group between 31-40 years. 46 percent of the study population were Hindus. Most of the study subjects (45 percent) were having secondary level education, were housewives (80 percent) and married (89 percent). 68 percent of the study population belonged to nuclear family. Maximum of the study population were from lower middle class (44 percent), 7 percent of the study subjects had a family history of breast cancer. Among the 100 respondents, 32 percent of them had inadequate knowledge, 53 percent of them had moderately adequate knowledge and only 15 percent of them had adequate knowledge on breast cancer. The range of knowledge score was between 0 - 40. The mean was 23.26 with a standard deviation of 8.9. There was no significant association between knowledge on breast cancer and demographic variables like age, religion, marital status, type of family, occupation and socio economic status. Education wise, moderately adequate knowledge on breast cancer was demonstrated by those who had graduate level and post graduate level of education (Chi - Square = 35.49). Conclusion: There is a need for developing health education programs about symptoms and early signs of breast cancer with emphasis on the importance of early breast cancer detection. Breast selfexamination, health education programs and mass media education should be targeted towards females in the age group between 21 years and above, ideally those 35 years of age and above. Further research regarding knowledge and practice of women towards breast cancer is recommended. [ABSTRACT FROM AUTHOR]

Breast cancer is one of the most common causes of cancer-related mortality globally, and its aggressive phenotype results in poor treatment outcomes. Growth Arrest-Specific 5 long non-coding RNA has attracted considerable attention due to its pivotal function in apoptosis regulation and tumor aggressiveness in breast cancer. Gas5 enhances apoptosis by regulating apoptotic proteins, such as caspases and BCL2 family proteins, and the sensitivity of BCCs to chemotherapeutic agents. At the same time, low levels of GAS5 increased invasion, metastasis, and overall tumor aggressiveness. GAS5 also regulates EMT markers, critical for cancer metastasis, and influences tumor cell proliferation by regulating various signaling components. As a result, GAS5 can be restored to suppress tumor development as a possible therapeutic strategy, which might present promising prospects for a patient's treatment. Its activity levels might also be a crucial indicator and diagnostic parameter for prediction. This review highlights the significant role of GAS5 in modulating apoptosis and tumor aggressiveness in breast cancer, emphasizing its potential as a therapeutic target for breast cancer treatment and management. [ABSTRACT FROM AUTHOR]

Peritoneal metastasis is the main cause of poor prognoses and high mortality in ovarian cancer patients. Abnormal protein glycosylation modification is associated with cancer malignancy. Elevated α1,3-mannosyltransferase 3 (ALG3), which catalyzes the α1,3-mannosylation of glycoproteins, has been found in some malignant tumors. However, the pathological significance of ALG3 and its regulatory mechanism in ovarian cancer metastasis is unclear. The results showed that the level of ALG3/α1,3-mannosylation was higher in human ovarian cancer tissues compared with normal ovarian tissues, as measured by Lectin chip, Western blot and Lectin blot analyses, as well as ovarian tissue microarray analysis. ALG3 was also correlated with the poor prognosis of ovarian cancer patients, according to survival analysis. The downregulation of ALG3 decreased the proliferation, stemness and peritoneal metastasis of ovarian cancer cells. The increase in urokinase plasminogen activator receptor (uPAR) α1,3-mannosylation catalyzed by ALG3 enhanced urokinase plasminogen activator (uPA)/uPAR activation and the interaction of uPAR with a disintegrin and metalloproteinase 8 (ADAM8), which promoted ovarian cancer peritoneal metastasis via the ADAM8/Ras/ERK pathway. Furthermore, decreased ALG3 suppressed ascites formation and the peritoneal metastasis of ovarian cancer cells in mice. This study highlights ALG3 as a potential diagnostic biomarker and prospective therapeutic target for ovarian cancer. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is one of the most common human malignancies accounting for approximately 10 % of worldwide cancer incidence and mortality. While early-stage CRC is mainly a preventable and curable disease, metastatic colorectal cancer (mCRC) remains an unmet clinical need. Moreover, about 25 % of CRC cases are diagnosed only at the metastatic stage. Despite the extensive molecular and functional knowledge on this disease, systemic therapy for mCRC still relies on traditional 5-fluorouracil (5-FU)-based chemotherapy regimens. On the other hand, targeted therapies and immunotherapy have shown effectiveness only in a limited subset of patients. For these reasons, there is a growing need to define the molecular and biological landscape of individual patients to implement novel, rationally driven, tailored therapies. In this review, we explore current and emerging approaches for CRC management such as genomic, transcriptomic and metabolomic analysis, the use of liquid biopsies and the implementation of patients' preclinical avatars. In particular, we discuss the contribution of each of these tools in elucidating patient specific features, with the aim of improving our ability in advancing the diagnosis and treatment of colorectal tumors. [ABSTRACT FROM AUTHOR]

Gastric cancer is one of the most common malignancies worldwide and has been identified as the third leading cause of cancer-related mortality. Flotillin-1 is a lipid raft-associated scaffolding protein and plays an important role in the progression and development of several malignant carcinomas. Flotillin-1 is involved in epithelial-mesenchymal transition (EMT) process of several solid tumors to promote metastasis. However, the detailed characteristics and mechanisms of Flotillin-1 in gastric cancer have rarely been investigated. In this study, we found Flotillin-1 upregulated in gastric cancer, and the high expression of Flotillin-1 correlated with a worse prognosis. The migration and invasion ability of gastric cancer cells was upregulated by overexpressing Flotillin-1. Knockdown of Flotillin-1 inhibits gastric cancer cells metastasis. Flotillin-1 is a key regulator of EMT process and promotes gastric cancer cells metastasis through inducing EMT. Flotillin-1 may interact with a deubiquitinase to inhibit the ubiquitination of Snail in gastric cancer cells to promote EMT process. Our study provides a rationale and potential target for the treatment of gastric cancer. [ABSTRACT FROM AUTHOR]

Prostate-specific antigen (PSA) screening was associated with reductions in metastatic prostate cancer and prostate cancer mortality in a large European screening trial, but not in a similar United States screening trial. There exists ongoing debate about the benefits and harms of PSA screening. We sought to evaluate the association of county-level PSA screening rates with county-level incidence of metastatic prostate cancer and prostate cancer mortality in the United States. This ecological study used data from the 2004-2012 Behavioral Risk Factor Surveillance System (BRFSS) to build a multilevel mixed effects model with poststratification using US Census data to estimate county-level PSA screening rates for all 3,143 United States counties adjusted for age, race, ethnicity, and county-level poverty rates. The exposure of interest was average county-level estimated PSA screening rate from 2004-2012, defined as the proportion of men aged 40-79 who underwent PSA screening within the prior 2 years. The primary outcomes were age-adjusted incidence of regional/distant prostate cancer 2015-2019 and age-adjusted prostate cancer mortality 2016-2020, the most recently available county-level prostate cancer outcome data. 416,221 male BRFSS respondents aged 40-79 met inclusion criteria and were used in the multilevel mixed effects model. The model was post-stratified using 63.4 million men aged 40-79 from all 3,143 counties in the 2010 Decennial Census. County-level estimated PSA screening rates exhibited geographic variability (Figure 1) and were pooled at the state level for internal validation with direct BRFSS state-level estimates, showing strong correlation with Pearson correlation coefficients 0.77-0.90. A 10% higher county-level probability of PSA screening 2004-2012 was associated with 14% lower county-level incidence of regional/distant prostate cancer 2015-2019 (rate ratio 0.86, 95% CI 0.85-0.87, p<0.001, Figure 2) and 10% lower county-level prostate cancer mortality 2016-2020 (rate ratio 0.90, 95% CI 0.89-0.91, p<0.001). This population-based ecological study found that United States counties with higher rates of PSA screening had lower rates of metastatic prostate cancer and prostate cancer mortality at extended follow-up. These findings may inform shared decision-making regarding PSA screening. [ABSTRACT FROM AUTHOR]

Our study measures the impact of diagnosing cancers early before they metastasise on reducing the burden of cancer death. A cohort of 716 501 people aged 15 to 89 years diagnosed with a solid cancer in New South Wales, Australia, during 1985 to 2014 were followed‐up to December 2015. Crude probabilities of cancer death by stage at diagnosis were calculated for all solid cancers combined and five individual cancers using flexible parametric relative survival models. These probabilities were used to estimate the number of avoided cancer deaths within 10 years of diagnosis in three 10‐year diagnostic periods if all cases with known distant stage were instead diagnosed at an earlier stage. Cancers are known to be diagnosed at distant stage composed ~16% of all solid cancers diagnosed during 2005 to 2014. Assuming all these cases were instead diagnosed at regional stage, an annual average of 2064 cancer deaths would have been potentially avoided within 10 years of diagnosis. This equated to ~21% of modelled observed deaths. Alternatively, if half of all known distant cases diagnosed during 2005 to 2014 were diagnosed as regional and half as localised, the average number of deaths avoided per year would increase to 2677 (~28%). Estimates varied by diagnostic period, sex and cancer type, reflecting both the different stage distributions for the cancer types, and the respective survival differences between cancer stages. While prevention is the most effective pillar of cancer control, these findings quantify the potential benefits of diagnosing all cancer types when they are less advanced to reduce the burden of cancer mortality. [ABSTRACT FROM AUTHOR]