Metastasis Of Different Types Research Articles

Dual inhibition of atypical PKC signaling and PI3K/Akt signaling dysregulates c-Myc to induce apoptosis in clear cell Renal Cell Carcinoma.

Renal Cell Carcinoma (RCC) is the most common type of kidney cancer (85%). 75% of the RCC cases involve conventional clear cell RCC (ccRCC). Approximately, 39% of late-stage patients (stage IV) are treated with chemotherapeutic agents. Phosphatidylinositol-3-kinase (PI3K) and Mitogen-Activated Protein Kinase Kinase (MEK)/extracellular signal-regulated kinase (ERK1/2) pathways are frequently activated in RCC. In addition, atypical PKCs (PKC-ί and PKC ζ) are overexpressed in most cancer cells, and they play a central role in tumor progression and the metastasis of different types of cancers. Our goal is to establish the role of aPKCs in the regulation of multiple key activated pathways in ccRCC. In this study, we also established a novel therapeutic regimen for dual inhibition of key activated pathways. In this study, 786-0 and Caki-1 cells were studied and subjected to cell viability assay, western blot analysis, scratch & wound healing assay, transwell invasion assay, immunofluorescence, immunoprecipitation, flow cytometry, and quantitative real-time polymerase chain reaction. We used combination of PI3K inhibitor- Alpelisib (BYL719) and ICA-1 (a PKC-ι-specific 5-amino-1-2,3-dihydroxy-4-(methylcyclopentyl)-1H-imidazole-4-carboxamide). In addition to drug treatment, small interfering RNA (siRNA) technology was used to further confirm the experimental outcome of the drug treatment. Our results suggest that treatment of ccRCC cells with a combination of ICA-1 (aPKC inhibitor) and BYL719 (PI3K inhibitor) downregulates PKC-ί and causes downstream inhibition of c-Myc. Inhibition of the PKCί also reduces activation of MEK/ERK1/2. It is observed that treatment with ICA-1 disrupts the level of the aPKC-Akt1 association. ICA-1 treatment also shows a reduced level of association between aPKC and c-Myc. The inhibition of aPKCs and downstream effector proteins by combination therapy is more pronounced compared to a single therapy. These effects contribute to reduced cell growth, and eventually, the induction of apoptosis. The decreased level of N-cadherin, p-vimentin, and vimentin and the increased level of E-cadherin confirm reduced malignancy. Therefore, implementing a combination of Alpelisib and a PKC-ι inhibitor is an effective approach to reducing cell proliferation, and invasion that eventually induces apoptosis and may be considered as a potential therapeutic option in ccRCC.

The Role of 68Ga FAPI-04 and 18F-FDG PET/CT in Detecting Liver Metastases in Different Types of Cancer.

We compared the diagnostic accuracies of 68Ga FAPI-04 PET/CT and 18F-FDG PET/CT for detecting liver metastases (LMs) in patients with different cancer types. This retrospective study included 63 patients with liver lesions who underwent 18F-FDG PET/CT and 68Ga-FAPI-04 PET/CT between May 2020 and May 2022. Patients with histopathologically confirmed primary diagnoses, data that could be accessed retrospectively, liver lesions confirmed by biopsy over at least 3-6 months of follow-up (via ultrasonography, CT, magnetic resonance imaging, PET/CT, or laboratory tests) were included. Patients with secondary malignancies or primary liver malignancies, and/or who could not be followed-up, were excluded. Of the 63 total patients, 34 (54%) were female, and the mean age was 61 (30-92) years. There were 582 LMs in 51 patients and 35 benign liver lesions in 20 (12 patients had only benign and 8 both benign and malignant lesions). Of the 582 LMs, 472 (81.1%) evidenced 18F-FDG uptake and 572 (98.2%) 68Ga-FAPI uptake. The diagnostic accuracies of 68Ga-FAPI PET/CT and 18F-FDG PET/CT were 98% and 82%, respectively (p < 0.001; McNemar test). When the LMs were compared, the maximum standardized uptake (SUVmax) value was significantly higher on 18F-FDG PET/CT than 68Ga-FAPI PET/CT (median: 6.0 vs. 5.4; p = 0.016). However, the LM-to-background ratio (TBR) was significantly higher on 68Ga-FAPI PET/CT than 18F-FDG PET/CT (median: 4.1 vs. 2.1; p < 0.001). 68Ga-FAPI PET/CT detected more LMs than did 18F-FDG PET/CT, and TBR was significantly higher on 68Ga-FAPI PET/CT than 18F-FDG PET/CT.

Silencing the Long Non-coding RNA HOTAIR Inhibits Epithelial-Mesenchymal Transition in MKN45 Gastric Cancer Cell Line by Downregulation of Fibronectin-1 and Claudin-4

Background: Gastric cancer is one of the most prevalent human malignancy-related death worldwide, which is usually diagnosed at the advanced stages resulting in metastasis. Recent studies have revealed that long non-coding RNAs (lncRNAs), which are known as non-coding RNAs, play a significant role in creating variety of molecular pathways (e.g., growth, proliferation, differentiation, and apoptosis) and negatively contribute to many unusual processes, including human cancers. The HOX antisense intergenic RNA (HOTAIR) is one of the novel non-coding RNAs which has recently emerged as a promoter of metastasis in different types of human cancers through epithelial-to-mesenchymal transition (EMT) process. Epithelial-to-mesenchymal transition (EMT) is a cellular process where an epithelial cell could change its phenotype to mesenchymal condition, which plays a crucial role in promoting cell invasion, angiogenesis, and metastases. Methods: This study aimed to explore the effect of HOTAIR gene silencing on the expression levels of two main markers of EMT signaling pathway, fibronectin (FN1) and claudin4 (CLDN4) in MKN45 cellular model of gastric cancer. The MKN45 cells were subjected to HOTAIR specific siRNA for 48 hours, and the extracted RNAs were subjected to cDNA synthesis and real-time PCR. The expression change was calculated using 2-ΔΔct. Results: Our findings showed that FN1 and CLDN4 were upregulated in MKN45 cells. Following the transfection of cell by HOTAIR siRNA, both FN1 and CLDN4 genes were significantly downregulated. Conclusions: HOTAIR long non-coding RNA may have regulated the expression levels of FN1 and CLDN4 genes in EMT signaling pathway. However, it was recommended that further experimental analyses should be carried out to confirm this observation. In other word, our study result may not have been applied as a therapeutic access until additional experiments were conducted.

MicroRNA-137 inhibits pituitary prolactinoma proliferation by targeting AKT2.

Prolactinoma is the most common type of pituitary adenoma. Most prolactinoma need medical treatment, but some of them are aggressive and require surgery. In previous decades, some miRNAs have been manifested as oncogenes or tumor suppressors. Consequently, miRNAs' abnormal expression involves tumorigenesis, invasion, and metastasis of different types of tumors, including pituitary tumors. The current study aim to explore the aggressiveness-associated miRNAs in prolactinoma and underlying molecular mechanisms based on the bioinformatic analysis and fundamental experiment studies. GSE46294 miRNA expression profile from the Gene Expression Omnibus (GEO) database was downloaded. Differentially expressed miRNAs (DEMs) were filtered from this data. Subsequently, the target genes of downregulated miRNAs were analyzed by Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. RT-qPCR, western blot, and CCK-8 assays were used to validate the effect of miR-137 on the proliferation of MMQ cells through AKT2. Finally, the binding site of rat miR-137 to AKT2were predicted by Targetscan andBibiserv database, and verified by double luciferase reporter assay. Twenty-four changed DEMs (fourteen upregulated and ten downregulated) were identified. Target genes of downregulated DEMs were classified into three groups by GO terms. KEGG pathway enrichment analysis revealed these target genes enriched in the PI3K-Akt pathway. We also confirmed that miR-137 can target AKT2 and inhibit the proliferation of MMQ cells induced by AKT2. MiR-137 suppressed prolactinomas' aggressive behavior by targeting AKT2.

Identification of ISCA1 as novel immunological and prognostic biomarker for bladder cancer.

BackgroundIron-sulfur cluster assembly 1 (ISCA1) has a significant effect on respiratory complexes and energy metabolism. Although there is some evidence that ISCA1 gene expression impacts energy metabolism and consequently has a role in tumorigenesis and cancer metastasis in different types of malignancies, no systematic pan-cancer study of the ISCA1 has been conducted. As a result, we sought to investigate ISCA1’s predictive value in 33 cancer types as well as its possible immunological function.MethodsWe included the pan-cancer expression profile dataset and clinical data from the public database. Firstly, the single-sample Gene Set Enrichment Analysis (ssGSEa) approach was employed for analyzing the immune link in pan-cancer, while the limma package was utilized for analyzing the differential expression in cancer species. Subsequently, ciberport, MCP-counter, TIMER2, quanTIseq, and xCELL were employed for analyzing bladder cancer (BLCA)’s immune infiltration. Least absolute shrinkage and selection operator (Lasso) were employed for choosing the best gene to develop the immune risk scoring model.Results ISCA1 gene expression was positively related to four immune signatures (chemokine, immunostimulator, MHC, and receptor) in BLCA. Samples of BLCA were sorted into two groups by the best cut-off of ISCA1 expression degree. The group with a high level of ISCA1 expression had a higher risk, suggesting that the ISCA1 gene was a risk factor in BLCA, and its high expression resulted in a poorer prognosis. Additionally, it was noted that ISCA1 was positively linked with these immune checkpoints. Moreover, there was a considerable positive link between ISCA1 and different immune properties in subgroups with different immune checkpoint inhibiting responses. Finally, an immune risk scoring model was made and it showed a better score in comparison to that of TIDE.Conclusion ISCA1 can be a prognostic marker for a variety of cancers, particularly BLCA. Its high level of expression has a deleterious impact on the prognosis of BLCA patients. This strongly shows that ISCA1 is a significant prognostic factor for BLCA and that it could be used as a new prognostic detection target and treatment approach.

Abstract SY41-02: Epigenetic influence of our (fatty) diet on metastatic-initiating cells: Role of intra-tumor Schwann cells

Abstract We have recently identified the cells uniquely responsible for the formation of metastasis in different types of human tumors. These cells have intriguing characteristics: i) they form primary lesions as efficiently as their tumor-initiating counterparts, but are exclusive in their ability to generate metastases; ii) they express the fatty acid translocase CD36, and are characterized by a unique lipid metabolic signature; iii) they are exquisitely sensitive to the levels of fat in circulation, and consequently, they relate the predisposition of metastasis directly to the content of dietary fat; iv) they are highly sensitive to CD36 inhibition, which almost completely abolishes their metastatic potential in preclinical models. In my talk, I will present our latest data on the molecular characterization of metastatic-initiating cells. I will place special emphasis showing how specific dietary lipids exert a striking long-term epigenetic effect over metastatic-initiating cells related to activation of intra-tumor Schwann cells, putting forward a novel concept of ¨metastatic epigenetic memory¨ elicited by our diet. Citation Format: Salvador Aznar-Benitah. Epigenetic influence of our (fatty) diet on metastatic-initiating cells: Role of intra-tumor Schwann cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr SY41-02.

Early Metastasis in Different Types of Breast Carcinoma - A Personal Experience

Background: Carcinoma breast is one of the leading causes of death in woman today and is the most common cancer among women. More than 2.3 million of women are diagnosed breast cancer each year world-wide. Carcinoma breast may present from an extent of non-palpable lump to a fixed mass with distal metastasis. As presentation is highly variable, management strategy varies even in same stage of disease.&#x0D; Objective: To identify early metastasis of different types of breast carcinoma and its management.&#x0D; Materials and methods: This is a prospective type of observational study in 100 cases done in the different surgical units of Dhaka Medical College Hospital (DMCH), Bangabandhu Sheikh Mujib Medical University (BSMMU) and Bashundhara Ad-din Medical College Hospital (BAMCH).Patients were selected clinically and by some standard investigation (FNAC and core biopsy) from January 2006 to December 2018.&#x0D; Result: Patients at different age groups had suffered from different types of breast carcinoma. Early diagnosis by triple assessments and proper surgical and post-surgical managements reduced both loco- regional and distant metastasis and also reduced both morbidity as well as mortality. Results of treatment and histopathological reports were recorded. It was found that FNAC is cheap and minimally invasive diagnostic procedure with high sensitivity (100%) and specificity (95%).Core needle biopsy is more accurate tissue diagnostic in breast cancer. Down staging has profound symptomatic and cosmetic benefit. In renders inoperable tumors become operable and reduce morbidities.&#x0D; Conclusion: Early diagnosis and treatment is the mainstay to achieve satisfactory outcome. Screening program especially Self-Breast Examination (SBE) is very much helpful in early diagnosis of disease in our social setting. Screening mammography has had the most substantial impact on the early diagnosis of, and subsequent decrease in mortality from breast carcinoma. Women of 20-40 years of age should have a breast examination every 2-3 yearly. Women of more than 40 years of age should have a breast examination every yearly.&#x0D; AKMMC J 2022; 13(1) : 14-21

Plasma Exosomes of Patients with Breast and Ovarian Tumors Contain an Inactive 20S Proteasome.

Exosomes are directly involved in governing of physiological and pathological conditions of an organism through the transfer of information from producing to receiving cells. It can be assumed that exosomes are one of the key players of tumor dissemination since they are very stable and small enough to penetrate from various tissues into biological fluids and then back, thus interacting with tissue target cells. We evaluated the enzymatic activity and the level of 20S proteasome in tissue and exosomes of healthy females (n = 39) and patients with ovarian (n = 50) and breast (n = 108) tumors to reveal the critical role of exosomal cargo in the mediation of different types of metastases. Exosomes from plasma and ascites were isolated and characterized in according to International Society for Extracellular Vesicles guidelines. The level of 20S proteasome in tissue and exosomes was determined using Western blot analysis. Chymotrypsin- and caspase-like (ChTL and CL, respectively) peptidase activities of the proteasomes were determined using fluorogenic Suc-LLVY-AMC and Cbz-LLG-AMC substrates, respectively. We observed increased levels of 20S proteasome in ovarian cancer tissue and luminal B subtype breast cancer tissue as well as in plasma exosomes from cancer patients. Moreover, the level of the 20S proteasome in plasma exosomes and ascites exosomes in patients with ovarian tumors is comparable and higher in ovarian cancer patients with low volume ascites than in patients with moderate and high-volume ascites. We also found increased ChTL and CL activities in breast cancer and ovarian cancer tissues, as well as in peritoneal metastases in ovarian cancer, while proteasomal activity in exosomes from plasma of healthy females and all patients, as well as from ascites of ovarian tumor patients were lower than detection limit of assay. Thus, regardless of the type of tumor metastasis (lymphogenous or peritoneal), the exosomes of cancer patients were characterized by an increased level of 20S proteasome, which do not exhibit enzymatic activity.

The Role of WAVE2 Signaling in Cancer.

The Wiskott–Aldrich syndrome protein (WASP) and WASP family verprolin-homologous protein (WAVE)—WAVE1, WAVE2 and WAVE3 regulate rapid reorganization of cortical actin filaments and have been shown to form a key link between small GTPases and the actin cytoskeleton. Upon receiving upstream signals from Rho-family GTPases, the WASP and WAVE family proteins play a significant role in polymerization of actin cytoskeleton through activation of actin-related protein 2/3 complex (Arp2/3). The Arp2/3 complex, once activated, forms actin-based membrane protrusions essential for cell migration and cancer cell invasion. Thus, by activation of Arp2/3 complex, the WAVE and WASP family proteins, as part of the WAVE regulatory complex (WRC), have been shown to play a critical role in cancer cell invasion and metastasis, drawing significant research interest over recent years. Several studies have highlighted the potential for targeting the genes encoding either part of or a complete protein from the WASP/WAVE family as therapeutic strategies for preventing the invasion and metastasis of cancer cells. WAVE2 is well documented to be associated with the pathogenesis of several human cancers, including lung, liver, pancreatic, prostate, colorectal and breast cancer, as well as other hematologic malignancies. This review focuses mainly on the role of WAVE2 in the development, invasion and metastasis of different types of cancer. This review also summarizes the molecular mechanisms that regulate the activity of WAVE2, as well as those oncogenic pathways that are regulated by WAVE2 to promote the cancer phenotype. Finally, we discuss potential therapeutic strategies that target WAVE2 or the WAVE regulatory complex, aimed at preventing or inhibiting cancer invasion and metastasis.

Nomogram based on homogeneous and heterogeneous associated factors for predicting distant metastases in patients with colorectal cancer

BackgroundThe identification of the homogeneous and heterogeneous risk factors for different types of metastases in colorectal cancer (CRC) may shed light on the aetiology and help individualize prophylactic treatment. The present study characterized the incidence differences and identified the homogeneous and heterogeneous risk factors associated with distant metastases in CRC.MethodsCRC patients registered in the SEER database between 2010 and 2016 were included in this study. Logistic regression was used to analyse homogeneous and heterogeneous risk factors for the occurrence of different types of metastases. Nomograms were constructed to predict the risk for developing metastases, and the performance was quantitatively assessed using the receiver operating characteristics (ROC) curve and calibration curve.ResultsA total of 204,595 eligible CRC patients were included in our study, and 17.07% of them had distant metastases. The overall incidences of liver metastases, lung metastases, bone metastases, and brain metastases were 15.34%, 5.22%, 1.26%, and 0.29%, respectively. The incidence of distant metastases differed by age, gender, and the original CRC sites. Poorly differentiated grade, more lymphatic metastasis, higher carcinoembryonic antigen (CEA), and different metastatic organs were all positively associated with four patterns of metastases. In contrast, age, sex, race, insurance status, position, and T stage were heterogeneously associated with metastases. The calibration and ROC curves exhibited good performance for predicting distant metastases.ConclusionsThe incidence of distant metastases in CRC exhibited distinct differences, and the patients had homogeneous and heterogeneous associated risk factors. Although limited risk factors were included in the present study, the established nomogram showed good prediction performance.

Diffusion-Weighted Imaging of Brain Metastasis: Correlation of MRI Parameters with Histologic Type.

To compare the diffusion properties of brain metastases as imaging biomarkers in various types of tumours, to determine their histology and origin. Magnetic Resonance Imaging (MRI) and diffusion-weighted imaging (DWI) were used to retrospectively study the data of 143 patients suffering from brain metastases. Four categories of primary tumours with metastases to the brain were included: lung carcinoma (n=102, 71.3%); breast carcinoma (n=27, 18.8%); colon carcinoma (n=8, 5.6%); and others (n=6, 4.2%). The Apparent Diffusion Coefficient (ADCmin ) values, as well as the normalised ADC ratio (nADC), were determined. The lesions on the DWI were categorised as follows: type 1, with negative findings on DWI; type 2, which were isointense with the normal cortical grey matter; type 3, which were hyperintense compared to the normal cortical grey matter. The diffusion type, mean ADCmin, and mean nADC showed statistically significant differences in different types of metastases. In the subgroup analysis, it was found that type 3 was the diffusion type found most extensively in the brain metastases of small cell carcinoma (SCLC) (n=52, 65.8%, p < 0.000). Furthermore, the mean ADCmin and nADC values were the least for the brain metastases of the SCLC (552.0 ± 134.2 and nADC = 0.8 ± 0.1, p < 0.000, respectively). The value of the mean ADCmin was low in the human epidermal growth factor receptor 2 (HER-2) negative groups than in the HER-2 positive groups at 786.8 ± 299.1 vs 844.8 ± 141.3 (p < 0.006). Our findings indicated that there is a correlation between diffusion parameters as imaging biomarkers of the solid component of brain metastases of primary tumours and the tumour histology.

Inflammation and Inflammasomes: Pros and Cons in Tumorigenesis.

Over the past decade, it has been well established that tumorigenesis is affected by chronic inflammation. During this event, proinflammatory cytokines are produced by numerous types of cells, such as fibroblasts, endothelial cells, macrophages, and tumor cells, and are able to promote the initiation, progression, and metastasis of different types of cancer. When persistent inflammation occurs, activation of inflammasome complexes is initiated, leading to its assembly and further activation of caspase, production of proinflammatory cytokines, and pyroptosis induction. The function of this multiprotein complex is not only to reassure inflammation and to promote cell death, through caspase activity, but also has been identified to have significant contributions during tumorigenesis and cancer development. So far, many efforts have been made in order to extend the knowledge of inflammasome implications and how its components could be targeted as therapeutic agents. Additionally, microRNAs (miRNAs), evolutionary conserved noncoding molecules, have emerged as pivotal players during numerous biological events by regulating gene and protein expression. Therefore, dysregulations of miRNA expressions have been correlated with inflammation during tumor development. In this review, we aim to highlight the dual role of inflammasomes and proinflammatory cytokines during carcinogenesis paired with the distinguished effects of miRNAs upon inflammation cascades during tumor growth and progression.

Talin-1 Gene Expression as a Tumor Marker in Hepatocellular Carcinoma Patients: A Pilot Study

Background &amp; Aims: Hepatocellular Carcinoma (HCC) is the most common primary liver tumor. It is the second most common cancer in men and the sixth in women in Egypt. One of the proteins participating in the trans-endothelial migration is Talin-1. It also has a role in the formation and metastasis of different types of cancer. This study aimed to evaluate the diagnostic impact of Talin-1 gene expression in HCC Egyptian patients. Methods: Our study included forty HCC patients, thirty liver cirrhosis patients without HCC and thirty healthy subjects. For all groups, clinical and biochemical parameters were investigated. Tumor characteristics were assessed and tumor staging was done using Okuda, CLIP, VISUM and Tokyo staging systems. In addition, Serum Alpha-Fetoprotein (AFP) levels were assayed using Enzyme Immunoassay (EIA) and Talin-1 gene expression was assessed in the Peripheral Blood Mononuclear Cells (PBMCs) via quantitative real-time Polymerase Chain Reaction (PCR). Results: Talin-1 gene expression was significantly upregulated in HCC patients in comparison to cirrhotic and control subjects. The Receiver Operating Characteristic (ROC) analysis indicated that Talin-1 gene expression surpasses serum levels of AFP in the diagnosis of HCC. In particular, the cut off value of 9.5 (2-∆∆Ct) recorded an AUC of 85.7% with a sensitivity of 93.3% and specificity of 80%. Conclusion: Our data confirmed an évident diagnostic role of Talin-1 gene expression for HCC detection.

Development of a nine-lncRNA signature as a novel prognostic marker of estrogen receptor-negative breast cancer.

Long non-coding RNAs (lncRNAs) have been demonstrated to be aberrantly expressed in several types of tumor, and dysregulated lncRNAs are suggested to play a prognostic role in breast cancer (BC). Estrogen receptor (ER) status is a prognostic factor in patients with ER-negative BC, which is associated with poor prognosis. Thus, the present study developed a prognostic lncRNA signature specifically for ER-negative BC, in order to predict the risk of post-surgery relapse and improve patient prognosis. A gene expression profile containing 1,631 lncRNAs was obtained by investigating and integrating publicly available cohorts of BC. Subsequently, a nine-lncRNA signature was developed and validated in two independent cohorts via the Cox regression model. Using the nine-lncRNA signature, patients in the discovery cohort were divided into high- and low-risk groups, with significantly different disease-free survival [DFS; hazard ratio (HR)=2.718, 95% confidence interval (CI)=2.115-3.494, P<0.0001]. Receiver operating characteristic curve analyses demonstrated that the area under the curve reached 0.908. Similar results were obtained in the two independent cohorts (HR=1.499, 95% CI=0.950-2.365, P=0.04; HR=1.262, 95% CI=1.056-1.510, P=0.01), respectively. Furthermore, the nine lncRNAs were demonstrated to play important roles in the cell invasion and metastasis of different types of tumor. The differentially expressed genes (DEGs) identified between the high- and low-risk groups were consistently high in the discovery and validation cohorts. Functional analysis indicated that these DEGs, as well as genes co-expressed with the nine lncRNAs, were involved in cancer-associated signaling pathways, all of which provide further evidence for the predictive ability of the nine-lncRNA signature. Overall, the present study developed a novel prognostic biomarker for ER-negative BC.

Adrenal metastases - long-term results of surgical treatment, single-centre experience.

IntroductionThe adrenal gland is a frequent site of metastases in different types of cancer. The aim of this study was to assess the results of metastatic adrenalectomy in a single institution and to identify factors for survival.Material and methodsA retrospective, single-centre analysis of outcomes of 39 patients (22 male, 17 female) with adrenal metastases who underwent surgery within 14 years (2004–2017) was performed. The median age at the time of adrenal surgery was 64.8 years (range 49–79 years).ResultsIn our study group non-small cell lung cancer (NSCLC) was the most frequent primary tumour type (15 pts), followed by renal cell carcinoma (RCC) (14 pts) and colon cancer (6 pts). Most of the metastases – 36 (92%) – were metachronous (> 6 months). All synchronous metastases were NSCLC. The mean time from primary cancer to adrenalectomy was 42.3 months (range 1–176) and was statistically longer for RCC. In 3 patients (8%) metastases were bilateral and both adrenal glands were removed. In all patients, surgery was limited to the adrenal gland, and no major complications of surgery were observed. The median overall survival after metastasectomy was 18 months (3–81) and was statistically longer for colon cancer – 29.5 months (p = 0.012). In patients who died, tumours were significantly bigger than in survivors, 76.5 mm vs. 52.5 mm (p = 0.026).ConclusionsSurgery for adrenal metastasis is safe and indications for this procedure should be individualized. In selected patients, surgical removal of adrenal metastasis was associated with longer survival.

G Protein-Coupled Receptors (GPCRs)-Mediated Calcium Signaling in Ovarian Cancer: Focus on GPCRs activated by Neurotransmitters and Inflammation-Associated Molecules

G-coupled protein receptors (GCPR) involve several signaling pathways, some of them being coupled with intracellular calcium (Ca2+) mobilization. GPCRs were involved in migration, invasion and metastasis of different types of cancers, including ovarian cancer. Many studies have discussed the essential contribution of GPCRs activated by steroid hormones in ovarian cancer. However, ovarian cancer is also associated with altered signals coming from the nervous system, the immune system or the inflammatory environment, in which GPCRs are ‘sensing’ these molecular signals. Many studies have been oriented so far on ovarian cell lines (most of them being of human cell lines), and only few studies based on animal models or clinical studies have been devoted to the expression changes or functional role of GPCRs in ovarian cancer. In this paper, we review the alterations of GPCRs activated by neurotransmitters (muscarinic receptors, serotonin receptors, dopamine receptors, adrenoceptors) or inflammation-associated molecules (bradykinin receptors, histamine receptors, chemokine receptors) in ovarian cancer and we discuss their potential as histological biomarkers.

MCT4 has a potential to be used as a prognostic biomarker - a systematic review and meta-analysis.

The role of several metabolic changes, such as hypoxia and acidosis, in the tumour environment has caught the attention of researchers in cancer progression and invasion. Lactate transport is one of the acidosis-enhancing processes that are mediated via monocarboxylate transporters (MCTs). We conducted a systematic review and meta-analysis to investigate the expression of two cancer-relevant MCTs (MCT1 and MCT4) and their potential prognostic significance in patients with metastasis of different types of cancer. Studies were included if they reported the number of metastatic tissue samples expressing either low or high levels of MCT1 and/or MCT4 or those revealing the hazard ratios (HRs) of the overall survival (OS) or disease-free survival (DFS) as prognostic indicators. During the period between 2010 and 2018, a total of 20 articles including 3831 patients (56.3% males) were identified. There was a significant association between MCT4 expression (high versus low) and lymph node metastasis [odds ratio (OR)=1.87, 95% confidence interval (CI)=1.10-3.17, P=0.02] and distant metastasis (OR=2.18, 95%CI=1.65-2.86, P<0.001) and the correlation remained significant for colorectal and hepatic cancer in subgroup analysis. For survival analysis, patients with shorter OS periods exhibited a higher MCT4 expression [hazard ratio (HR)=1.78, 95%CI=1.49-2.13, P<0.001], while DFS was shorter in patients with high MCT1 (HR=1.48, 95%CI=1.04-2.10, P=0.03) and MCT4 expression (HR=1.70, 95%CI=1.19-2.42, P=0.003) when compared to their counterparts with low expression levels. Future research studies should consider the pharmacologic inhibition of MCT4 to effectively inhibit cancer progression to metastasis.

Abstract 4189: Limited-versus-extensive staging system for small cell prostate cancer

Abstract Introduction: Small cell prostate cancer (SCPC) is one of the most common extrapulmonary small cell cancers as well as one of the most common histology type among non-adenocarcinoma prostate cancers. While small cell lung cancer follows a limited-versus-extensive staging system which is different from the stage I to IV system used for non-small cell lung cancer, the prostate adenocarcinoma staging system is used in SCPC despite its distinct clinical feature and aggressive disease course. Limited by the rarity of SCPC, the optimal staging strategy for SCPC remains unknown. The present study aimed to investigate the prognostic value of limited-vs-extensive staging system in SCPC patients. Method: The Surveillance, Epidemiology, and End Results database was used to analyze the incidence and outcome of small cell prostate cancer. Patients diagnosed between the year 2004 through 2015 were included. Limited stage is defined as those without metastasis regardless of degree of local invasion. Extensive stage is defined as any metastasis to locoregional lymph node, to distant lymph node, or to distant organs. Result: A total of 364 SCPC patients are included in the study cohort, accounting for 0.05% of all prostate cancer cases (n=665,054). Age adjusted incidence of SCPC was 0.959 per 1,000,000 per year over the whole study period. The median age at diagnosis of SCPC is 71 years. The median overall survival is 9 months. In the 322 patients with known metastasis status, 243 (75.5%) patients are in extensive stage, whereas 79 patients are in limited stage. Patients in extensive stage are more likely to have PSA level greater than 20 than those in limited stage (26.3% vs 6%), but a similar proportion of patients in both groups have PSA level less than 4 (44.3% vs 40.0%). Compared to patients with extensive stage, those with limited stage disease had a significantly better overall survival (17 months vs 9 months, p&amp;lt;0.001) as well as disease specific survival (28 months vs 11 months, p&amp;lt;0.001). Limited stage patients with different T stage had a similar overall survival (p=0.43). Similarly, all extensive stage patients had similar outcome despite different types of metastasis (p=0.40). Multivariable analysis of treatment showed that only chemotherapy is associated with improved survival in extensive stage disease with HR of 0.46. Conclusion: SCPC patients can be staged to limited stage and extensive stage based on the absence versus presence of metastasis. T stage in limited stage patient and type of metastasis in extensive stage patient is not associated with different outcome. Citation Format: Salman Syed, Faisal Ali, Spyridon Basourakos, Zimu Gong. Limited-versus-extensive staging system for small cell prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4189.

Quantification of A Spectrum of Adhesion Molecules in Metastatic Cancer Patient Samples Using a Multiplex Bead-Based Immunoassay Panel

Abstract Metastasis to distant organs is responsible for ~90% of cancer-related deaths. Adhesion molecules are cell surface proteins that mediate the interactions between disseminated tumor cells and the endothelium of blood vessels present in the tumor microenvironment, and thus play a major role in tumor metastasis. Serum and plasma samples from patients with metastatic disease (head, neck, breast, pancreatic, gastric, and lung cancer patients) or healthy controls were assayed with a bead-based multiplex immunoassay which measured the concentration levels of the following adhesion molecules: ICAM-1, ICAM-2, ICAM-3, VCAM-1, PECAM-1, ALCAM-1, EpCAM, NCAM, E-selectin, P-selectin, L-selectin, PSGL-1, and CD44. Although limited by sample size, differential concentrations of assay targets were detected between healthy and disease-state samples. We have demonstrated that this multiplex panel is a robust tool for measuring the concentration of a spectrum of adhesion molecules with great efficiency and convenience. This panel will help screen and identify the adhesion molecules that may be universally or specifically involved in metastasis of different types of cancer.

Breaking down the Contradictory Roles of Histone Deacetylase SIRT1 in Human Breast Cancer.

Breast cancer (BC) is the most common type of cancer in women worldwide; it is a multifactorial genetic disease. Acetylation and deacetylation are major post-translational protein modifications that regulate gene expression and the activity of a myriad of oncoproteins. Aberrant deacetylase activity can promote or suppress tumorigenesis and cancer metastasis in different types of human cancers, including breast cancer. Sirtuin-1 (SIRT1) is a class-III histone deacetylase (HDAC) that deacetylates both histone and non-histone targets. The often-described ‘regulator of regulators’ is deeply implicated in apoptosis, gene regulation, genome maintenance, DNA repair, aging, and cancer development. However, despite the accumulated studies over the past decade, the role of SIRT1 in human breast cancer remains a subject of debate and controversy. The ambiguity surrounding the implications of SIRT1 in breast tumorigenesis stems from the discrepancy between studies, which have shown both tumor-suppressive and promoting functions of SIRT1. Furthermore, studies have shown that SIRT1 deficiency promotes or suppresses tumors in breast cancer, making it an attractive therapeutic target in cancer treatment. This review provides a comprehensive examination of the various implications of SIRT1 in breast cancer development and metastasis. We will also discuss the mechanisms underlying the conflicting roles of SIRT1, as well as its selective modulators, in breast carcinogenesis.