Nutritional AGEing and RAGEing as a Regulator of the Tumor Microenvironment

Abstract Objectives Advanced glycation end products (AGEs) are reactive metabolites formed endogenously by glyoxidative, oxidative and lipoxidative stresses. Foods associated with modern dietary habits are particularly AGE laden but despite increasing epidemiological evidence for oncogenic potential, cause and effect relationships are lacking. The objective was to provide detailed mechanistic insight and in vivo confirmation that AGEs found in the diet are oncogenic drivers of tumorigenesis. Methods We used the heat driven formation of glyoxidative, oxidative and lipoxidative stresses in experimental mouse chow to reproduce the wide spectrum of the AGEs found in vivo. Syngeneic xenograft and spontaneous prostate and breast cancer mouse models were then fed the AGE specific diets and the effects of chronic AGE consumption on tumor growth assessed. To gain mechanistic insight, human and mouse two compartment co-culture models using primary fibroblasts and matched tumor epithelial cells were then used to assess the effects of AGEs on extracellular crosstalk in the TME. Results A high impact finding from our research is that consumption of AGEs found in our diet promotes prostate tumor growth, aggression and metastasis by functioning as ligand to the transmembrane receptor for AGE (RAGE). Dietary-AGEs promoted neoplastic growth by functioning as ligand to RAGE expressed in the prostate tumor stroma not tumor epithelium. Dietary-AGE activation of stromal RAGE caused a regulatory program of ‘activated fibroblasts’ defined by the increased expression of cancer associated fibroblast markers, NFkB, MYC and pro-tumorigenic paracrine secretion. Fibroblast activation was accompanied by decreased expression of androgen receptor (AR) and the increased expression of neuroendocrine differentiation markers in tumor epithelial cells. AGE exposed primary fibroblasts isolated from patient tissue conferred tumor promoting abilities when cultured with patient matched tumor epithelial cells. Conclusions For the first time these data demonstrate a direct cause and effect relationship between dietary-AGEs and neoplastic growth. This may lay the foundation for strategic self-management strategies aimed at reducing AGE exposure in the diet to reduce cancer incidence and mortality. Funding Sources NIH/NCI; ACS.

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Consumption of Dietary Advanced Glycation End Products Promotes Prostate Tumor Growth by Creating a Tumor Enhancing Stromal Microenvironment

Current Developments in Nutrition ◽

10.1093/cdn/nzaa044_058 ◽

2020 ◽

Vol 4 (Supplement_2) ◽

pp. 359-359

Author(s):

David Turner ◽

Bradley Krisanits ◽

Callan Frye ◽

Lourdes Nogueira ◽

Ried Schuster ◽

...

Keyword(s):

Epithelial Cells ◽

Tumor Growth ◽

Advanced Glycation End Products ◽

Prostate Tumor ◽

Migration And Invasion ◽

Advanced Glycation ◽

Neoplastic Growth ◽

Incidence And Mortality ◽

Glycation End Products ◽

End Products

Abstract Objectives The literature regarding the role of advanced glycation end products (AGEs) on tumor biology has shown only moderate promise reflected by increases in cell growth, migration and invasion in vitro which is not supported by increased tumor growth in vivo14-16– A caveat to these studies is that they are centered upon a single AGE peptide and a subsequent assessment of their molecular effects on tumor epithelial cells. The objective is to show that by feeding mice a high AGE diet we can recapitulate a microenvironment comprising of a wide spectrum of AGEs which can influence neoplastic growth. Methods We recapitulated a dietary-AGE induced microenvironment in syngeneic xenograft and spontaneous breast and prostate mouse cancer models and the effects on tumor growth assessed. The mechanistic consequences of dietary-AGEs on the tumor microenvironment were further defined using mouse and human primary and immortalized two-compartment co-culture ex vivo culture models. Results Dietary-AGE consumption in breast and prostate tumor models significantly accelerated tumor growth by functioning as ligand to the transmembrane receptor for AGE (RAGE). Our studies demonstrate that AGEs promote neoplastic growth by functioning as ligand to RAGE expressed in the tumor stroma not the tumor epithelial cells. Dietary-AGE activation of RAGE in both breast and prostate tumors caused a regulatory program of ‘activated fibroblasts’ defined by increased expression of cancer associated fibroblast markers, NFkB and MYC upregulation, and pro-tumorigenic paracrine secretion. Complementary to this, our published studies show that high intake of dietary AGE after BCa diagnosis increases risk of mortality in postmenopausal women. Conclusions These data demonstrate, for the first time, the oncogenic potential of dietary-AGEs in promoting neoplastic growth. This lays the foundation for strategic changes aimed at reducing cancer incidence and mortality as pharmacological, educational and/or interventional strategies aimed at reducing the dietary-AGE accumulation pool may one day be viewed as universal cancer preventative and/or therapeutic initiatives especially when combined with existing therapies. Funding Sources David P. Turner was supported by grants from the NIH/NCI, R21 CA194469 and U54 CA21096..

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Estrogen exhibits a biphasic effect on prostate tumor growth through the ERβ-KLF5 pathway

Molecular and Cellular Biology ◽

10.1128/mcb.00625-15 ◽

2015 ◽

pp. MCB.00625-15 ◽

Cited By ~ 7

Author(s):

Yuka Nakajima ◽

Asami Osakabe ◽

Tsuyoshi Waku ◽

Takashi Suzuki ◽

Kensuke Akaogi ◽

...

Keyword(s):

Prostate Cancer ◽

Tumor Growth ◽

Cancer Progression ◽

Tumor Formation ◽

Prostate Tumor ◽

Biphasic Effect ◽

New Strategy ◽

17Β Estradiol ◽

Xenograft Models

Estrogens are effective in the treatment of prostate cancer; however, the effects of estrogens on prostate cancer are enigmatic. In this study, we demonstrated that estrogen (17β-estradiol, E2) has biphasic effects on prostate tumor growth. A lower dose of E2 increased tumor growth in mouse xenograft models using DU145 and PC-3 human prostate cancer cells, whereas a higher dose significantly decreased tumor growth. We found that anchorage-independent apoptosis in these cells was inhibited by E2 treatment. Similarly,in vivoangiogenesis was suppressed by E2. Interestingly, these effects of E2 were abolished by knockdown of either estrogen receptor β (ERβ) or Krüppel-like zinc-finger transcription factor 5 (KLF5). In addition, E2 suppressed KLF5-mediated transcription through ERβ, which inhibits pro-apoptoticFOXO1and pro-angiogenicPDGFAexpression. Furthermore, we revealed that a non-agonistic ER ligand GS-1405 inhibitedFOXO1andPDGFA expression through ERβ and KLF5 pathway, and regulated prostate tumor growth without ERβ transactivation. Therefore, these results suggest that E2 biphasically modulates prostate tumor formation by regulating KLF5-dependent transcription through ERβ and provide a new strategy for designing ER modulators, which will be able to regulate prostate cancer progression with minimal adverse effects due to ER transactivation.

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Inhibition of vimentin or β1 integrin reverts morphology of prostate tumor cells grown in laminin-rich extracellular matrix gels and reduces tumor growth in vivo

Molecular Cancer Therapeutics ◽

10.1158/1535-7163.mct-08-0544 ◽

2009 ◽

Vol 8 (3) ◽

pp. 499-508 ◽

Cited By ~ 48

Author(s):

Xueping Zhang ◽

Marcia V. Fournier ◽

Joy L. Ware ◽

Mina J. Bissell ◽

Adly Yacoub ◽

...

Keyword(s):

Extracellular Matrix ◽

Tumor Growth ◽

Tumor Cells ◽

Prostate Tumor ◽

Β1 Integrin ◽

Prostate Tumor Cells

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Hsp90-stabilized MIF supports tumor progression via macrophage recruitment and angiogenesis in colorectal cancer

Cell Death and Disease ◽

10.1038/s41419-021-03426-z ◽

2021 ◽

Vol 12 (2) ◽

Author(s):

Luisa Klemke ◽

Tiago De Oliveira ◽

Daria Witt ◽

Nadine Winkler ◽

Hanibal Bohnenberger ◽

...

Keyword(s):

Colorectal Cancer ◽

Epithelial Cells ◽

Tumor Growth ◽

Tumor Progression ◽

Hsp90 Inhibitor ◽

Growth Defects ◽

Macrophage Recruitment ◽

Upstream Regulator

AbstractMacrophage migration inhibitory factor (MIF) is an upstream regulator of innate immunity, but its expression is increased in some cancers via stabilization with HSP90-associated chaperones. Here, we show that MIF stabilization is tumor-specific in an acute colitis-associated colorectal cancer (CRC) mouse model, leading to tumor-specific functions and selective therapeutic vulnerabilities. Therefore, we demonstrate that a Mif deletion reduced CRC tumor growth. Further, we define a dual role for MIF in CRC tumor progression. Mif deletion protects mice from inflammation-associated tumor initiation, confirming the action of MIF on host inflammatory pathways; however, macrophage recruitment, neoangiogenesis, and proliferative responses are reduced in Mif-deficient tumors once the tumors are established. Thus, during neoplastic transformation, the function of MIF switches from a proinflammatory cytokine to an angiogenesis promoting factor within our experimental model. Mechanistically, Mif-containing tumor cells regulate angiogenic gene expression via a MIF/CD74/MAPK axis in vitro. Clinical correlation studies of CRC patients show the shortest overall survival for patients with high MIF levels in combination with CD74 expression. Pharmacological inhibition of HSP90 to reduce MIF levels decreased tumor growth in vivo, and selectively reduced the growth of organoids derived from murine and human tumors without affecting organoids derived from healthy epithelial cells. Therefore, novel, clinically relevant Hsp90 inhibitors provide therapeutic selectivity by interfering with tumorigenic MIF in tumor epithelial cells but not in normal cells. Furthermore, Mif-depleted colonic tumor organoids showed growth defects compared to wild-type organoids and were less susceptible toward HSP90 inhibitor treatment. Our data support that tumor-specific stabilization of MIF promotes CRC progression and allows MIF to become a potential and selective therapeutic target in CRC.

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Thrombin and Factor XII Drive Prostate Tumor Growth In Vivo

Blood ◽

10.1182/blood.v126.23.424.424 ◽

2015 ◽

Vol 126 (23) ◽

pp. 424-424

Author(s):

Gregory Adams ◽

Leah Rosenfeldt ◽

Malinda Frederick ◽

Keith Kombrinck ◽

Brett P. Monia ◽

...

Keyword(s):

Prostate Cancer ◽

Tumor Growth ◽

Tumor Cell ◽

Cancer Cells ◽

Prostate Tumor ◽

Coagulation Cascade ◽

Cancer Growth ◽

Factor Xii ◽

Contact Activation

Abstract Several hemostatic factors are known to strongly influence the metastatic process by promoting the survival of early metastases. Despite this consistent phenomenon observed across multiple tumor cell types and multiple procoagulant components of the hemostatic system, the role of hemostasis in the establishment and growth of primary tumors is highly context dependent. One clinically relevant context where coagulation appears to be important for tumor development/outgrowth is prostate cancer. Men on long-term anticoagulation appear to be at significantly lower risk for developing prostate cancer compared to men on short-term anticoagulation or those not on anticoagulation. Here, we report that multiple hemostatic proteases drive prostate tumor growth in vivo. To test the hypothesis that the central hemostatic protease, thrombin, promotes prostate tumor growth, mice with a life-long genetically-imposed diminution in circulating prothrombin levels (fIILox/-), or mice administered a prothrombin-specific antisense oligonucleotide (ASO) gapmer that limits prothrombin expression, were inoculated subcutaneously with the murine-derived prostatic adenocarcinoma cell line TRAMP-C2Re3 in parallel with appropriate controls. Genetically or pharmacologically lowering prothrombin expression significantly impeded prostate tumor growth. In complementary experiments, treatment with the prothrombin-specific ASO gapmer significantly impeded the growth of human-derived prostate cancer cells (PC3) in immunodeficient mice. Detailed histological analysis revealed that tumors harvested from mice with diminished prothrombin expression had significantly lower mitotic indices, suggesting that thrombin promotes tumor proliferation in vivo. Lowering prothrombin levels did not affect apoptosis, vascular density, or the presence of tumor-associated macrophages. Previous studies have indicated that tumor cell-associated tissue factor expression is one important mechanism by which cancer cells can locally generate thrombin. However, the relative importance of the contact pathway of coagulation system activation in cancer progression is less defined. In order to determine whether fXII plays a role in prostate cancer growth, mice challenged with prostate cancer were treated with a fXII-specific ASO gapmer or a control oligonucleotide with no homology in the murine genome in parallel. Remarkably, tumors from anti-fXII ASO gapmer treated mice were ~3-fold smaller than those harvested from control animals at the end of the ~3 week experiment. To our knowledge, this finding is the first demonstration that the contact system protease fXII plays a significant role in tumor growth. In sum, these data show that thrombin promotes the growth of prostate cancer, and suggest that contact activation of the coagulation cascade may be a critical factor in prostate cancer growth. Disclosures Monia: Isis Pharmaceuticals: Employment, Other: Shareholder. Revenko:SIS Pharmaceuticals Inc.: Employment.

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Knockdown of antizyme inhibitor decreases prostate tumor growth in vivo

Amino Acids ◽

10.1007/s00726-011-1032-x ◽

2011 ◽

Vol 42 (2-3) ◽

pp. 549-558 ◽

Cited By ~ 12

Author(s):

Rachelle R. Olsen ◽

Ivy Chung ◽

Bruce R. Zetter

Keyword(s):

Tumor Growth ◽

Prostate Tumor ◽

Antizyme Inhibitor

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Methaneseleninic acid and γ-Tocopherol combination inhibits prostate tumor growth in Vivo in a xenograft mouse model

Oncotarget ◽

10.18632/oncotarget.1979 ◽

2014 ◽

Vol 5 (11) ◽

pp. 3651-3661 ◽

Cited By ~ 9

Author(s):

Chandra K. Singh ◽

Mary A. Ndiaye ◽

Imtiaz A. Siddiqui ◽

Minakshi Nihal ◽

Thomas Havighurst ◽

...

Keyword(s):

Mouse Model ◽

Tumor Growth ◽

Prostate Tumor ◽

Xenograft Mouse Model

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Upregulation of Linc00284 Promotes Lung Cancer Progression by Regulating the miR-205-3p/c-Met Axis

Frontiers in Genetics ◽

10.3389/fgene.2021.694571 ◽

2021 ◽

Vol 12 ◽

Author(s):

Wang Sheng ◽

Weixi Guo ◽

Fang Lu ◽

Hongming Liu ◽

Rongmu Xia ◽

...

Keyword(s):

Lung Cancer ◽

Tumor Growth ◽

Cancer Progression ◽

Significant Negative Correlation ◽

Normal Lung ◽

Migration And Invasion ◽

Expression Levels ◽

Incidence And Mortality

Lung cancer (LC) is a malignant tumor with the highest incidence and mortality rates worldwide. Linc00284, a long non-coding RNA, is a newly discovered regulator of LC. This study aimed to explore the role of Linc00284 in LC progression. Gene expression levels were detected by RT-qPCR and/or western blot analysis. Cell migratory and invasive capabilities were measured by wound healing and transwell assays. Subcutaneous xenograft models were constructed to examine tumor growth of LC cells. Data showed that Linc00284 was significantly upregulated in LC tissues compared to adjacent normal lung tissues and predicted poor prognosis in patients with LC. In vitro, Linc00284 was highly expressed in LC cells and was mainly localized in the cytoplasm. Mechanistically, Linc00284 directly bound to miR-205-3p, leading to the upregulation of c-Met expression. A significant negative correlation was observed between Linc00284 and miR-205-3p expression levels, and the Linc00284 level was positively correlated with the c-Met expression. Linc00284/miR-205-3p/c-Met regulatory axis promotes LC cell proliferation, migration, and invasion. Furthermore, the in vivo results indicated that Linc00284 knockdown markedly suppressed tumor growth. Taken together, these data suggest that Linc00284 facilitates LC progression by targeting the miR-205-3p/c-Met axis, which may be a potential target for LC treatment.

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