The role of contortrostatin, a snake venom disintegrin, in the inhibition of tumor progression and prolongation of survival in a rodent glioma model

Macrophages supply iron to the breast tumor microenvironment by enforced secretion of lipocalin-2 (Lcn-2)-bound iron as well as the increased expression of the iron exporter ferroportin (FPN). We aimed at identifying the contribution of each pathway in supplying iron for the growing tumor, thereby fostering tumor progression. Analyzing the expression profiles of Lcn-2 and FPN using the spontaneous polyoma-middle-T oncogene (PyMT) breast cancer model as well as mining publicly available TCGA (The Cancer Genome Atlas) and GEO Series(GSE) datasets from the Gene Expression Omnibus database (GEO), we found no association between tumor parameters and Lcn-2 or FPN. However, stromal/macrophage-expression of Lcn-2 correlated with tumor onset, lung metastases, and recurrence, whereas FPN did not. While the total iron amount in wildtype and Lcn-2−/− PyMT tumors showed no difference, we observed that tumor-associated macrophages from Lcn-2−/− compared to wildtype tumors stored more iron. In contrast, Lcn-2−/− tumor cells accumulated less iron than their wildtype counterparts, translating into a low migratory and proliferative capacity of Lcn-2−/− tumor cells in a 3D tumor spheroid model in vitro. Our data suggest a pivotal role of Lcn-2 in tumor iron-management, affecting tumor growth. This study underscores the role of iron for tumor progression and the need for a better understanding of iron-targeted therapy approaches.

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Antioxidants Promote Intestinal Tumor Progression in Mice

Antioxidants ◽

10.3390/antiox10020241 ◽

2021 ◽

Vol 10 (2) ◽

pp. 241

Author(s):

Zhiyuan V. Zou ◽

Kristell Le Gal ◽

Ahmed E. El Zowalaty ◽

Lara E. Pehlivanoglu ◽

Viktor Garellick ◽

...

Keyword(s):

Oxidative Stress ◽

Colorectal Cancer ◽

Tumor Progression ◽

Human Subjects ◽

Plasma Concentrations ◽

Intestinal Tumor ◽

Adenomatous Polyposis ◽

Intestinal Tumors ◽

The Impact

Dietary antioxidants and supplements are widely used to protect against cancer, even though it is now clear that antioxidants can promote tumor progression by helping cancer cells to overcome barriers of oxidative stress. Although recent studies have, in great detail, explored the role of antioxidants in lung and skin tumors driven by RAS and RAF mutations, little is known about the impact of antioxidant supplementation on other cancers, including Wnt-driven tumors originating from the gut. Here, we show that supplementation with the antioxidants N-acetylcysteine (NAC) and vitamin E promotes intestinal tumor progression in the ApcMin mouse model for familial adenomatous polyposis, a hereditary form of colorectal cancer, driven by Wnt signaling. Both antioxidants increased tumor size in early neoplasias and tumor grades in more advanced lesions without any impact on tumor initiation. Importantly, NAC treatment accelerated tumor progression at plasma concentrations comparable to those obtained in human subjects after prescription doses of the drug. These results demonstrate that antioxidants play an important role in the progression of intestinal tumors, which may have implications for patients with or predisposed to colorectal cancer.

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FSMP-15. EVALUATING THE ROLE OF LONG-CHAIN FATTY ACID METABOLISM IN PROMOTING GLIOBLASTOMA GROWTH

Neuro-Oncology Advances ◽

10.1093/noajnl/vdab024.079 ◽

2021 ◽

Vol 3 (Supplement_1) ◽

pp. i19-i19

Author(s):

Divya Ravi ◽

Carmen del Genio ◽

Haider Ghiasuddin ◽

Arti Gaur

Keyword(s):

Fatty Acids ◽

Fatty Acid ◽

Survival Rate ◽

Tumor Progression ◽

Acid Synthesis ◽

Normal Brain ◽

Acid Uptake ◽

Exogenous Fatty Acid ◽

Long Chain

Abstract Glioblastomas (GBM) or Stage IV gliomas, are the most aggressive of primary brain tumors and are associated with high mortality and morbidity. Patients diagnosed with this lethal cancer have a dismal survival rate of 14 months and a 5-year survival rate of 5.6% despite a multimodal therapeutic approach, including surgery, radiation therapy, and chemotherapy. Aberrant lipid metabolism, particularly abnormally active de novo fatty acid synthesis, is recognized to have a key role in tumor progression and chemoresistance in cancers. Previous studies have reported a high expression of fatty acid synthase (FASN) in patient tumors, leading to multiple investigations of FASN inhibition as a treatment strategy. However, none of these have developed as efficacious therapies. Furthermore, when we profiled FASN expression using The Cancer Genome Atlas (TCGA) we determined that high FASN expression in GBM patients did not confer a worse prognosis (HR: 1.06; p-value: 0.51) and was not overexpressed in GBM tumors compared to normal brain. Therefore, we need to reexamine the role of exogenous fatty acid uptake over de novofatty acid synthesis as a potential mechanism for tumor progression. Our study aims to measure and compare fatty acid oxidation (FAO) of endogenous and exogenous fatty acids between GBM patients and healthy controls. Using TCGA, we have identified the overexpression of multiple enzymes involved in mediating the transfer and activation of long-chain fatty acids (LCFA) in GBM tumors compared to normal brain tissue. We are currently conducting metabolic flux studies to (1) assess the biokinetics of LCFA degradation and (2) establish exogenous versus endogenous LCFA preferences between patient-derived primary GBM cells and healthy glial and immune cells during steady state and glucose-deprivation.

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Lamin B1 promotes tumor progression and metastasis in primary prostate cancer patients

Future Oncology ◽

10.2217/fon-2020-0825 ◽

2020 ◽

Author(s):

Fei Luo ◽

Jiaxi Han ◽

Yatong Chen ◽

Kuo Yang ◽

Zhihua Zhang ◽

...

Keyword(s):

Prostate Cancer ◽

Tumor Progression ◽

Cancer Metastasis ◽

Disease Free Survival ◽

Free Survival ◽

Lamin B1 ◽

Kaplan Meier ◽

Primary Prostate Cancer ◽

Clinical Relationship

Aims: To determine the role of lamin B1 (LMNB1) in the progression and metastasis of primary prostate cancer (PC). Patients & methods: Two PC cohorts were used to investigate the clinical relationship between LMNB1 expression and tumor progression and metastasis. Results: The qRT-PCR results revealed that LMNB1 expression was markedly increased in patients with aggressive features and was associated with worse prognosis. Logistic regression analyses indicated that LMNB1 expression is an independent risk factor for distant metastasis. Kaplan–Meier analysis showed that increased LMNB1 levels were related to poor disease-free survival in the primary PC cohort. Conclusion: This study reveals that upregulation of LMNB1 is associated with cancer metastasis and poor survival outcomes in primary PC patients.

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Cell Plasticity and Prostate Cancer: The Role of Epithelial–Mesenchymal Transition in Tumor Progression, Invasion, Metastasis and Cancer Therapy Resistance

Cancers ◽

10.3390/cancers13112795 ◽

2021 ◽

Vol 13 (11) ◽

pp. 2795

Author(s):

Sofia Papanikolaou ◽

Aikaterini Vourda ◽

Spyros Syggelos ◽

Kostis Gyftopoulos

Keyword(s):

Prostate Cancer ◽

Cancer Therapy ◽

Tumor Progression ◽

Epithelial Mesenchymal Transition ◽

Metastatic Tumor ◽

Therapy Resistance ◽

Cellular Process ◽

Cell Plasticity ◽

Mesenchymal Transition

Prostate cancer, the second most common malignancy in men, is characterized by high heterogeneity that poses several therapeutic challenges. Epithelial–mesenchymal transition (EMT) is a dynamic, reversible cellular process which is essential in normal embryonic morphogenesis and wound healing. However, the cellular changes that are induced by EMT suggest that it may also play a central role in tumor progression, invasion, metastasis, and resistance to current therapeutic options. These changes include enhanced motility and loss of cell–cell adhesion that form a more aggressive cellular phenotype. Moreover, the reverse process (MET) is a necessary element of the metastatic tumor process. It is highly probable that this cell plasticity reflects a hybrid state between epithelial and mesenchymal status. In this review, we describe the underlying key mechanisms of the EMT-induced phenotype modulation that contribute to prostate tumor aggressiveness and cancer therapy resistance, in an effort to provide a framework of this complex cellular process.

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LOX-1 and cancer: an indissoluble liaison

Cancer Gene Therapy ◽

10.1038/s41417-020-00279-0 ◽

2021 ◽

Author(s):

M. Murdocca ◽

C. De Masi ◽

S. Pucci ◽

R. Mango ◽

G. Novelli ◽

...

Keyword(s):

Tumor Progression ◽

Epithelial Mesenchymal Transition ◽

Vascular Endothelial Cells ◽

Transition Process ◽

Receptor Protein ◽

Pancreatic Tumors ◽

Tumor Evolution ◽

Mesenchymal Transition ◽

Angiogenic Proteins

AbstractRecently, a strong correlation between metabolic disorders, tumor onset, and progression has been demonstrated, directing new therapeutic strategies on metabolic targets. OLR1 gene encodes the LOX-1 receptor protein, responsible for the recognition, binding, and internalization of ox-LDL. In the past, several studied, aimed to clarify the role of LOX-1 receptor in atherosclerosis, shed light on its role in the stimulation of the expression of adhesion molecules, pro-inflammatory signaling pathways, and pro-angiogenic proteins, including NF-kB and VEGF, in vascular endothelial cells and macrophages. In recent years, LOX-1 upregulation in different tumors evidenced its involvement in cancer onset, progression and metastasis. In this review, we outline the role of LOX-1 in tumor spreading and metastasis, evidencing its function in VEGF induction, HIF-1alpha activation, and MMP-9/MMP-2 expression, pushing up the neoangiogenic and the epithelial–mesenchymal transition process in glioblastoma, osteosarcoma prostate, colon, breast, lung, and pancreatic tumors. Moreover, our studies contributed to evidence its role in interacting with WNT/APC/β-catenin axis, highlighting new pathways in sporadic colon cancer onset. The application of volatilome analysis in high expressing LOX-1 tumor-bearing mice correlates with the tumor evolution, suggesting a closed link between LOX-1 upregulation and metabolic changes in individual volatile compounds and thus providing a viable method for a simple, non-invasive alternative monitoring of tumor progression. These findings underline the role of LOX-1 as regulator of tumor progression, migration, invasion, metastasis formation, and tumor-related neo-angiogenesis, proposing this receptor as a promising therapeutic target and thus enhancing current antineoplastic strategies.

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