Abstract 1217: Determining the impact of CRPC-specific p53 mutation on therapeutic response and prostate tumor progression

Background: (1) Endometrial cancer is one of the most common cancers affecting women, with a growing incidence. To better understand the different behaviors associated with endometrial cancer, it is necessary to understand the changes that occur at a molecular level. CD133 is one of the factors that regulate tumor progression, which is primarily known as the transmembrane glycoprotein associated with tumor progression or cancer stem cells. The aim of our study was to assess the impact of subcellular CD133 expression on the clinical course of endometrial cancer. (2) Methods: CD133 expression in the plasma membrane, nucleus, and cytoplasm was assessed by immunohistochemical staining in a group of 64 patients with endometrial cancer representing FIGO I-IV stages, grades 1–3 and accounting for tumor angioinvasion. (3) Results: Nuclear localization of CD133 expression was increased in FIGO IB-IV stages compared to FIGO IA. Furthermore, CD133 expression in the nucleus and plasma membrane is positively and negatively associated with a higher grade of endometrial cancer and angioinvasion, respectively. (4) Conclusions: Our findings suggest that positive nuclear CD133 expression in the tumor may be related to a less favorable prognosis of endometrial carcinoma patients and has emerged as a useful biomarker of a high-risk group.

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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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A bi-directional dialog between vascular cells and monocytes/macrophages regulates tumor progression

Cancer and Metastasis Reviews ◽

10.1007/s10555-021-09958-2 ◽

2021 ◽

Author(s):

Victor Delprat ◽

Carine Michiels

Keyword(s):

Tumor Progression ◽

Cancer Progression ◽

Cell Activation ◽

Molecular Mechanisms ◽

Immune Cell ◽

The Body ◽

Vascular Cells ◽

Tumor Associated Macrophage ◽

Immune Cell Activation ◽

The Impact

AbstractCancer progression largely depends on tumor blood vessels as well on immune cell infiltration. In various tumors, vascular cells, namely endothelial cells (ECs) and pericytes, strongly regulate leukocyte infiltration into tumors and immune cell activation, hence the immune response to cancers. Recently, a lot of compelling studies unraveled the molecular mechanisms by which tumor vascular cells regulate monocyte and tumor-associated macrophage (TAM) recruitment and phenotype, and consequently tumor progression. Reciprocally, TAMs and monocytes strongly modulate tumor blood vessel and tumor lymphatic vessel formation by exerting pro-angiogenic and lymphangiogenic effects, respectively. Finally, the interaction between monocytes/TAMs and vascular cells is also impacting several steps of the spread of cancer cells throughout the body, a process called metastasis. In this review, the impact of the bi-directional dialog between blood vascular cells and monocytes/TAMs in the regulation of tumor progression is discussed. All together, these data led to the design of combinations of anti-angiogenic and immunotherapy targeting TAMs/monocyte whose effects are briefly discussed in the last part of this review.

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The impact of C677T and A1298C MTHFR polymorphisms on methotrexate therapeutic response in East Bohemian region rheumatoid arthritis patients

Rheumatology International ◽

10.1007/s00296-015-3219-z ◽

2015 ◽

Vol 35 (7) ◽

pp. 1149-1161 ◽

Cited By ~ 14

Author(s):

Tomas Soukup ◽

Martin Dosedel ◽

Petr Pavek ◽

Jana Nekvindova ◽

Ivan Barvik ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Therapeutic Response ◽

Mthfr Polymorphisms ◽

The Impact

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Rad9 Protein Contributes to Prostate Tumor Progression by Promoting Cell Migration and Anoikis Resistance

Journal of Biological Chemistry ◽

10.1074/jbc.m112.402784 ◽

2012 ◽

Vol 287 (49) ◽

pp. 41324-41333 ◽

Cited By ~ 19

Author(s):

Constantinos G. Broustas ◽

Aiping Zhu ◽

Howard B. Lieberman

Keyword(s):

Cell Migration ◽

Tumor Progression ◽

Prostate Tumor ◽

Anoikis Resistance

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TP53 Action and the Consequences of TP53 Mutation in Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2019-121285 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. SCI-13-SCI-13

Author(s):

Scott W. Lowe

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Tp53 Mutation ◽

P53 Mutation ◽

Tp53 Mutations ◽

Genomic Analyses ◽

Equity Ownership ◽

Myeloid Neoplasia ◽

The Impact ◽

Acute Myeloid

p53 action and the consequences of p53 mutation in acute myeloid leukemia TP53 mutations are common in treatment associated myeloid neoplasia (tMN) and complex karyotype acute myeloid leukemia (CK-AML), where they are associated with chemoresistance and one of the worst prognoses of any leukemia genotype. To understand the impact of TP53 mutations on AML biology, we are performing arge scale genomic analyses of p53 mutant AML and have produced a series of animal models that appear to faithfully reflect molecular and biological features of the human disease. We have gone on to explore the biology of particular TP53 mutational configurations drive AML initiation and maintenance, and to identify and understanding the events that cooperate with p53 mutations during leukemogenesis. Disclosures Lowe: Blueprint Medicines: Consultancy, Equity Ownership; ORIC pharmaceuticals: Consultancy, Equity Ownership; Mirimus: Consultancy, Equity Ownership; Constellation Pharma: Consultancy, Equity Ownership; Petra Pharmaceuticals: Consultancy, Equity Ownership; PMV Pharmaceuticals: Consultancy, Equity Ownership; Faeth Therapeutics: Consultancy, Equity Ownership.

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NIR Bioluminescence Probe Enables Discovery of Diet-Induced Modulation of the Tumor Microenvironment via Nitric Oxide

10.26434/chemrxiv.14176835.v1 ◽

2021 ◽

Author(s):

Anuj K Yadav ◽

Michael C. Lee ◽

Melissa Lucero ◽

Christopher J. Reinhardt ◽

ShengZhang Su ◽

...

Keyword(s):

Nitric Oxide ◽

Tumor Microenvironment ◽

Tumor Progression ◽

Critical Role ◽

Cellular Systems ◽

Tissue Imaging ◽

Molecular Evidence ◽

No Production ◽

The Impact

Nitric oxide (NO) plays a critical role in acute and chronic inflammation. NO’s contributions to cancer are of particular interest due to its context-dependent bioactivities. For example, immune cells initially produce cytotoxic quantities of NO in response to the nascent tumor. However, it is believed that this fades over time and reaches a concentration that supports the tumor microenvironment (TME). These complex dynamics are further complicated by other factors, such as diet and oxygenation, making it challenging to establish a complete picture of NO’s impact on tumor progression. Although many activity-based sensing (ABS) probes for NO have been developed, only a small fraction have been employed in vivo and fewer yet are practical in cancer models where the NO concentration is < 200 nM. To overcome this outstanding challenge, we have developed BL660-NO, the first ABS probe for NIR bioluminescence imaging of NO in cancer. Owing to the low intrinsic background, high sensitivity, and deep tissue imaging capabilities of our design, BL660-NO was successfully employed to visualize endogenous NO in cellular systems, a human liver metastasis model, and a murine breast cancer model. Importantly, its exceptional performance facilitated the design of a dietary study to examine the impact of NO on the TME by varying the intake of fat. BL660-NO provides the first direct molecular evidence that intratumoral NO becomes elevated in mice fed a high-fat diet who became obese with larger tumors compared to control animals on a low-fat diet. These results indicate that an inflammatory diet can increase NO production via recruitment of macrophages and overexpression of iNOS which in turn can drive tumor progression.

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Modification of intrinsic ovarian cancer tumor factors by Wnt-pathway agents influences macrophage recruitment and activity.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e14514 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e14514-e14514

Author(s):

Jhalak Dholakia ◽

Carly Bess Scalise ◽

Ashwini A. Katre ◽

Rebecca Christian Arend

Keyword(s):

Ovarian Cancer ◽

Wnt Pathway ◽

Myeloid Cell ◽

Genetic Alterations ◽

P53 Mutation ◽

M2 Macrophage ◽

Macrophage Activity ◽

Macrophage Recruitment ◽

M1 Macrophage ◽

The Impact

e14514 Background: The Wnt/B-catenin pathway is associated with a “cold” phenotype in the gynecologic malignancy tumor microenvironment (TME), resulting in immunosuppression. Research is limited regarding this pathway’s effects on TME myeloid cell populations. We aimed to characterize the impact of Wnt pathway modulation on macrophage activity in ovarian cancer. Methods: Syngeneic murine models harboring ID8 parental (ID8par) tumors were treated with DKN-01 and CGX-1321 as single agents or in sequence (DKN-01 followed by CGX-1321.) Flow cytometry analyses were performed on harvested omenta and blood. Ascites from 10 high grade serous epithelial ovarian cancer patients were treated with DKN-01 (Wnt activator) or CGX-1321 (Wnt inhibitor) for 48 hours; multiplex cytokine array was performed to determine changes in cytokine/chemokine expression. Lastly, we performed co-culture analyses on the effects of ID8par and ID8p53-/- isolated cell media on murine macrophage (RAW264.7) activity. Results: In the ID8par model, sequential DKN-01/CGX-1321 resulted in the greatest macrophage influx into the TME. CGX-1321 monotherapy increased the M2:M1 macrophage ratio (pro-tumor) while DKN-01 monotherapy resulted in decreased M2:M1 ratio (anti-tumor.) In human ascites, DKN-01 increased macrophage colony stimulating factor (M-CSF) expression. Of note, ascites from a patient harboring a p53 mutation demonstrated an increase in M1 polarization cytokines IFNy and TNFa in response to DKN-01; CGX-1321 treatment resulted in increased M2 polarization cytokines IL-4 and IL-13. In co-culture analysis, ID8par isolated media increased RAW264.7 migration and polarization towards an M2 phenotype; ID8p53-/- isolated media polarized towards an M1 phenotype. Conclusions: Macrophage activity influences immune responses and tumor behavior. For example, M2 macrophages are pro-tumor and can enhance tumor growth and immune evasion. In our studies, we demonstrated that macrophage recruitment and polarization (M1 vs M2) are influenced by genetic alterations that can be modified by treatment. The ID8par model positively influenced M2 macrophage activity; ID8p53-/- cells positively influenced M1 macrophage activity. Importantly, DKN-01 treatment reverses the M2-dominant phenotype in ID8par model towards M1. These results suggest that p53 mutation and/or DKN-01 treatment in ovarian cancer influences M1 anti-tumor macrophage activity, and posits a novel targetable pathway. Further studies should investigate Wnt/B-catenin modulation on macrophage activity for immunotherapy in gynecologic malignancies.

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