Lactosyl-sepharose binding proteins from pancreatic cancer cells show differential expression in primary and metastatic organs.
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ABSTRACT:
SUBMITTER: Sagini MN
PROVIDER: S-EPMC7153218 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Pancreatic ductal adenocarcinoma (PDAC) is reported to be the third highest cause of cancer-related deaths in the United States. PDAC is known for its high proportion of stroma, which accounts for 90% of the tumor mass. The stroma is made up of extracellular matrix (ECM) and nonmalignant cells such as inflammatory cells, cancer-associated fibroblasts, and lymphatic and blood vessels. Here, we decoupled the effects of the ECM on PDAC cell lines by culturing cells on surfaces coated with different ECM proteins. Our data show that the primary tumor-derived cell lines have different morphology depending on the ECM proteins on which they are cultured, while metastatic lesion-derived PDAC lines' morphology does not change with respect to the different ECM proteins. Similarly, ECM proteins modulate the proliferation rate and the gemcitabine sensitivity of the primary tumor PDAC cell lines, but not the metastatic PDAC lines. Lastly, transcriptomics analysis of the primary tumor PDAC cells cultured on different ECM proteins reveals the regulation of various pathways, such as cell cycle, cell-adhesion molecules, and focal adhesion, including the regulation of several integrin genes that are essential for ECM recognition.
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Project description:BACKGROUND:With the improvement of treatment and prognosis for patients with late malignant diseases, certain malignancies with distant metastasis (M1 category) have been further classified into M1a (single metastatic site) and M1b (multiple metastatic sites) category in the staging system. We aimed to assess the feasibility of sub-classifying metastatic pancreatic adenocarcinoma (mPA) into M1a and M1b category depending on the number of metastatic organs. METHODS:Patient records were collected from the Surveillance, Epidemiology, and End Results (SEER) database (2010-2015). Univariable and multivariable analyses were performed using the Cox regression model. Then survival analysis was determined using the Kaplan-Meier method. RESULTS:A total of 11,885 patients were included in this analysis, including 9425 patients with single metastasis and 2460 patients with multiple metastases. Multivariable analysis showed that gender, age, marital status, grade, surgery, chemotherapy, and radiotherapy were independent prognostic factors for patients with single metastasis; gender, age, marital status, grade, chemotherapy and radiotherapy were independent prognostic factors for patients with multiple metastases. Notably, surgery was an independent prognostic factor for patients with single metastasis (P?<?0.001) but not for patients with multiple metastases (P?=?0.134). Kaplan-Meier analysis showed that patients with single metastasis (M1a) had better survival outcomes than patients with multiple metastases (M1b) (P?<?0.001). CONCLUSIONS:PA patients with M1 diseases could be divided into M1a (single metastasis) category and M1b (multiple metastases) category by the number of metastatic organs. The subclassification would facilitate individualized treatment for late PA patients. Surgery was associated with lower mortality in M1a patients but not significantly in M1b patients.
| S-EPMC7457242 | biostudies-literature
Project description:Pancreatic cancer is the fourth leading cause of cancer related deaths in the United States with a five-year survival rate of 6%. It is characterized by extremely aggressive tumor growth rate and high incidence of metastasis. One of the most common and profound biochemical phenotypes of animal and human cancer cells is their ability to metabolize glucose at high rates, even under aerobic conditions. However, the contribution of metabolic interrelationships between tumor cells and cells of the surrounding microenvironment to the progression of cancer is not well understood. We evaluated differential expression of metabolic genes and, hence, metabolic pathways in primary tumor and metastases of patients with pancreatic adenocarcinoma.We analyzed the metabolic gene (those involved in glycolysis, tri-carboxylic acid pathway, pentose-phosphate pathway and fatty acid metabolism) expression profiles of primary and metastatic lesions from pancreatic cancer patients by gene expression arrays. We observed two principal results: genes that were upregulated in primary and most of the metastatic lesions; and genes that were upregulated only in specific metastatic lesions in a site-specific manner. Immunohistochemical (IHC) analyses of several metabolic gene products confirmed the gene expression patterns at the protein level. The IHC analyses also revealed differential tumor and stromal expression patterns of metabolic enzymes that were correlated with the metastasis sites.Here, we present the first comprehensive studies that establish differential metabolic status of tumor and stromal components and elevation of aerobic glycolysis gene expression in pancreatic cancer.
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Project description:Background:Pancreatic cancer is the fourth leading cause of cancer related deaths the United States with a five-year survival rate of 6% (1). It is characterized by extremely aggressive tumor growth rate and high incidence of metastasis. One of the most common and profound biochemical phenotypes of animal and human cancer cells is their ability to metabolize glucose at high rates, even under aerobic conditions (2-5). However, the contribution of metabolic interrelationships between tumor cells and cells of the surrounding microenvironment to the progression of cancer is not well understood. We evaluated differential expression of metabolic genes and hence, metabolic pathways in primary tumor and metastases of patients with pancreatic adenocarcinoma. Methods and Findings:We analyzed the metabolic gene (those involved in glycolysis, tri-carboxylic acid pathway, pentose-phosphate pathway and fatty acid metabolism) expression profiles of primary and metastatic lesions from 35 pancreatic cancer patients by Affymetrix expression arrays. We observed two principal results: genes that were upregulated in primary and most of the metastatic lesions; and genes that were upregulated only in specific metastatic lesions in a site-specific manner. Immunohistochemical (IHC) analyses of several metabolic gene products confirmed the gene expression patterns at the protein level. The IHC analyses also revealed differential tumor and stromal expression patterns of metabolic enzymes that were correlated with the metastasis sites. Conclusions: Here, we present the first comprehensive studies that establish differential metabolic status of tumor and stromal components and elevation of aerobic glycolysis gene expression in pancreatic cancer. Furthermore, we identify key metabolic genes that can be targeted to diminish overall cancer progression and others that can be targeted to prevent cancer metastasis at specific organ sites. reference x sample
| S-ECPF-GEOD-34153 | biostudies-other
Project description:Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease. Circulating tumor cells (CTC) in the blood are hypothesized as the means of systemic tumor spread. Blood obtained from healthy donors and patients with PDAC was therefore subject to size-based CTC-isolation. We additionally compared Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations in pancreatic CTC and corresponding tumors, and evaluated their significance as prognostic markers. Samples from 68 individuals (58 PDAC patients, 10 healthy donors) were analyzed; CTCs were present in patients with UICC stage IA-IV tumors and none of the controls (p?<?0.001). Patients with >3?CTC/ml had a trend for worse median overall survival (OS) than patients with 0.3–3?CTC/ml (P?=?0.12). Surprisingly, CTCs harbored various KRAS mutations in codon 12 and 13. Patients with a KRAS G12V mutation in their CTC (n?=?14) had a trend to better median OS (24.5 months) compared to patients with other (10 months), or no detectable KRAS mutations (8 months; P?=?0.04). KRAS mutations in CTC and corresponding tumor were discordant in 11 of 26 “tumor-CTC-pairs” (42%), while 15 (58%) had a matching mutation; survival was similar in both groups (P?=?0.36). Genetic characterization, including mutations such as KRAS, may prove useful for prognosis and understanding of tumor biology.
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Project description:BackgroundMolecular profiling is increasingly used to match patients with metastatic cancer to targeted therapies, but obtaining a high-quality biopsy specimen from metastatic sites can be difficult.MethodsPatient samples were received by Perthera to coordinate genomic, proteomic and/or phosphoproteomic testing, using a specimen from either the primary tumour or a metastatic site. The relative frequencies were compared across specimen sites to assess the potential limitations of using a primary tumour sample for clinical decision support.ResultsNo significant differences were identified at the gene or pathway level when comparing genomic alterations between primary and metastatic lesions. Site-specific trends towards enrichment of MYC amplification in liver lesions, STK11 mutations in lung lesions and ATM and ARID2 mutations in abdominal lesions were seen, but were not statistically significant after false-discovery rate correction. Comparative analyses of proteomic results revealed significantly elevated expression of ERCC1 and TOP1 in metastatic lesions.ConclusionsTumour tissue limitations remain a barrier to precision oncology efforts, and these real-world data suggest that performing molecular testing on a primary tumour specimen could be considered in patients with pancreatic adenocarcinoma who do not have adequate tissue readily available from a metastatic site.
| S-EPMC6738081 | biostudies-literature
Project description:PurposePancreatic ductal adenocarcinoma (PDAC) is characterized by high levels of fibrosis, termed desmoplasia, which is thought to hamper the efficacy of therapeutics treating PDAC. Our primary focus was to evaluate differences in the extent of desmoplasia in primary tumors and metastatic lesions. As metastatic burden is a primary cause for mortality in PDAC, the extent of desmoplasia in metastases may help to determine whether desmoplasia targeting therapeutics will benefit patients with late-stage, metastatic disease.Experimental designWe sought to assess desmoplasia in metastatic lesions of PDAC and compare it with that of primary tumors. Fifty-three patients' primaries and 57 patients' metastases were stained using IHC staining techniques.ResultsWe observed a significant negative correlation between patient survival and extracellular matrix deposition in primary tumors. Kaplan-Meier curves for collagen I showed median survival of 14.6 months in low collagen patients, and 6.4 months in high-level patients (log rank, P < 0.05). Low-level hyaluronan patients displayed median survival times of 24.3 months as compared with 9.3 months in high-level patients (log rank, P < 0.05). Our analysis also indicated that extracellular matrix components, such as collagen and hyaluronan, are found in high levels in both primary tumors and metastatic lesions. The difference in the level of desmoplasia between primary tumors and metastatic lesions was not statistically significant.ConclusionsOur results suggest that both primary tumors and metastases of PDAC have highly fibrotic stroma. Thus, stromal targeting agents have the potential to benefit PDAC patients, even those with metastatic disease.
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Project description:Pancreatic cancer is a challenging malignancy with limited treatment options and poor life expectancy. The only curative option is surgical resection, but only 15%-20% of patients are resectable at presentation because more than 50% of patients has distant metastasis at diagnosis and the rest of them has locally advanced pancreatic cancer (LAPC). The standard of care first line treatment for LAPC patients is chemotherapy with or without radiation therapy. Recent developments in minimally invasive ablative techniques may add to the treatment armamentarium of LAPC. There are increasing number of studies evaluating these novel ablative techniques, including radiofrequency ablation, microwave ablation, cryoablation and irreversible electroporation. Most studies which included pancreatic tumor ablation, demonstrated improved overall survival in LAPC patients. However, the exact protocols are yet to set up to which stage of the treatment algorithm ablative techniques can be added and in what kind of treatment combinations. Patients with metastatic pancreatic cancer has dismal prognosis with 5-year survival is only 3%. The most common metastatic site is the liver as 90% of pancreatic cancer patients develop liver metastasis. Chemotherapy is the primary treatment option for patients with metastatic pancreatic cancer. However, when the tumor is not responding to chemotherapy or severe drug toxicity develops, locoregional liver-directed therapies can provide an opportunity to control intrahepatic disease progression and improve survival in selected patients. During the last decade new therapeutic options arose with the advancement of minimally invasive technologies to treat pancreatic cancer patients. These new therapies have been a topic of increasing interest due to the severe prognostic implications of locally advanced and metastatic pancreatic cancer and the low comorbid risk of these procedures. This review summarizes new ablative options for patients with LAPC and percutaneous liver-directed therapies for patients with liver-dominant metastatic disease.
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