Hypoxic control of metastasis

In the paper

“LOX regulates osteoclastogenesis”

What the sources say

• Supported

  The passage labeled Abstract reports that recombinant LOX stimulated osteoclastogenesis in pre-osteoclast cultures, generating more osteoclasts than RANKL stimulation. It concludes that LOX can stimulate the generation of fully differentiated, active osteoclasts independently of RANKL. (LLM, conf=0.93)

  cites [96] Cox TR Nature 2015 522 106 110 26017313 PMC4961239 source

In the paper

“Hypoxia and activation of HIF signaling influence multiple steps within the metastatic cascade, including invasion and migration, intravasation and extravasation, and establishment of the premetastatic niche, as well as survival and growth at the distant site”

What the sources say

• Not checked yetcites [48] De Bock K Mazzone M Carmeliet P Nat. Rev. Clin. Oncol 2011 8 393 404 21629216 source
• Not checked yetcites [49] Semenza GL Biochim. Biophys. Acta 2016 1863 382 391 26079100 PMC4678039 source

In the paper

“The hypoxia-inducible transcription factors HIF-1 and HIF-2 coordinate the adaptive cellular response to low oxygen tensions by activating gene expression programs controlling glucose uptake, metabolism, angiogenesis, erythropoiesis, cell proliferation, differentiation, and apoptosis”

What the sources say

• Not checked yetcites [1] Semenza GL Cell 2012 148 399 408 22304911 PMC3437543 source

In the paper

“Hypoxia is a potent microenvironmental factor promoting metastatic progression.”

In the paper

“HIF signaling in malignant cells influences multiple steps within the metastatic cascade.”

In the paper

“This hydroxylation event allows the von Hippel–Lindau tumor suppressor protein (VHL), the substrate recognition component of an E3 ubiquitin ligase complex, to bind to HIF-α and target it for proteasomal degradation”

What the sources say

• Not checked yet

  A check is scheduled.

  cites [10] Jaakkola P Science 2001 292 468 472 11292861 source
• Not checked yetcites [11] Ivan M Science 2001 292 464 468 11292862 source
• Not checked yetcites [12] Maynard MA J. Biol. Chem 2003 278 11032 11040 12538644 source
• Not checked yetcites [13] Maxwell PH Nature 1999 399 271 275 10353251 source
• Not checked yetcites [14] Tanimoto K Makino Y Pereira T Poellinger L EMBO J 2000 19 4298 4309 10944113 PMC302039 source

In the paper

“Hypoxia activates HIF signaling by promoting the protein stability of HIF-α subunits.”

What the sources say

• Not checked yetcites [7] Epstein AC Cell 2001 107 43 54 11595184 source
• Not checked yetcites [8] Bruick RK McKnight SL Science 2001 294 1337 1340 11598268 source
• Not checked yetcites [9] Ivan M Proc. Natl. Acad. Sci. U.S.A 2002 99 13459 13464 12351678 PMC129695 source

In the paper

“Under normoxic conditions, prolyl hydroxylase enzymes (EGLN 1–3, also known as PHD 1–3) use oxygen as a substrate to hydroxylate key proline residues within the HIF-1 and HIF-2 α subunits”

What the sources say

• Not checked yetcites [7] Epstein AC Cell 2001 107 43 54 11595184 source
• Not checked yetcites [8] Bruick RK McKnight SL Science 2001 294 1337 1340 11598268 source
• Not checked yetcites [9] Ivan M Proc. Natl. Acad. Sci. U.S.A 2002 99 13459 13464 12351678 PMC129695 source

In the paper

“In the nucleus, HIF-α subunits dimerize with aryl hydrocarbon receptor nuclear translocator (ARNT) and bind to hypoxia-responsive elements in target genes to activate gene transcription by recruiting transcriptional coactivators including p300/CBP”

What the sources say

• Not checked yetcites [15] Schödel J Blood 2011 117 e207 e217 21447827 PMC3374576 source
• Not checked yetcites [16] Wang GL Jiang BH Rue EA Semenza GL Proc. Natl. Acad. Sci. U.S.A 1995 92 5510 5514 7539918 PMC41725 source
• Not checked yetcites [17] Wang GL Semenza GL Proc. Natl. Acad. Sci. U.S.A 1993 90 4304 4308 8387214 PMC46495 source

In the paper

“Hundreds of genes are activated in response to HIF-1 and HIF-2”

In the paper

“Additionally, PHD activity can be inhibited by reactive oxygen species (ROS) produced by the mitochondria”

What the sources say

• Not checked yetcites [21] Majmundar AJ Wong WJ Simon MC Mol. Cell 2010 40 294 309 20965423 PMC3143508 source
• Not checked yetcites [23] Kaelin WG Jr. Cell Metab 2005 1 357 358 16054083 source

In the paper

“The enzymatic activity of the EGLN 1–3 requires iron and 2-oxoglutarate to hydroxylate the HIF-α subunits.”

In the paper

“In addition, most sporadic ccRCCs lose VHL function through genomic alterations”

What the sources say

• Not checked yetcites [25] Gnarra JR Nat. Genet 1994 7 85 90 7915601 source

In the paper

“loss of polycomb repressive complex 2 (PRC2)–dependent histone H3 Lys-27 trimethylation activates HIF-mediated chemokine (C-X-C motif) receptor 4 (CXCR4) expression to promote invasion and metastasis”

What the sources say

• Not checked yetcites [26] Vanharanta S Nat. Med 2013 19 50 56 23223005 PMC3540187 source

In the paper

“epigenetic modifications within prometastatic genes allow for enhanced expression of metastasis-associated HIF target genes”

What the sources say

• Not checked yetcites [26] Vanharanta S Nat. Med 2013 19 50 56 23223005 PMC3540187 source

In the paper

“VHL activity in tumors can be regulated by WSB1, an E3 ligase that targets pVHL for ubiquitination and proteasomal degradation”

What the sources say

• Not checked yetcites [27] Kim JJ Genes Dev 2015 29 2244 2257 26545811 PMC4647558 source

In the paper

“Goto et al. recently identified the ubiquitin C-terminal hydrolase-L1 (UCHL1) as a HIF-1 deubiquitinating enzyme that promotes HIF-1 activity under normoxic and hypoxic conditions by preventing VHL-mediated degradation of HIF-1”

What the sources say

• Not checked yetcites [35] Goto Y Nat. Commun 2015 6 6153 25615526 PMC4317501 source

In the paper

“suggesting that UCHL1 may promote metastasis through HIF”

What the sources say

• Not checked yetcites [35] Goto Y Nat. Commun 2015 6 6153 25615526 PMC4317501 source

In the paper

“genetic inactivation of HIF-1 in UCHL1-overexpressing cells reversed the metastatic potential of these cells”

What the sources say

• Not checked yetcites [35] Goto Y Nat. Commun 2015 6 6153 25615526 PMC4317501 source

In the paper

“Additionally, activation of PI3K and AKT signaling through growth factor receptor signaling can promote HIF-α stabilization and activity under normoxic conditions”

What the sources say

• Not checked yetcites [32] Laughner E Taghavi P Chiles K Mahon PC Semenza GL Mol. Cell. Biol 2001 21 3995 4004 11359907 PMC87062 source
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [33] Zhong H Cancer Res 2000 60 1541 1545 10749120

In the paper

“Inactivating mutations in phosphatase and tensin homolog (PTEN) or the tuberosis sclerosis complex (TSC) complex, as well as activating mutations in phosphatidylinositol 3-kinase (PI3K) or AKT, lead to increased TORC1 activity that promotes HIF-α stabilization”

What the sources say

• Not checked yetcites [22] Kaelin WG Jr. Cold Spring Harb. Symp. Quant. Biol 2011 76 335 345 22089927 PMC4197849 source
• Not checked yetcites [28] Hudson CC Mol. Cell. Biol 2002 22 7004 7014 12242281 PMC139825 source
• Not checked yetcites [29] Arsham AM Howell JJ Simon MC J. Biol. Chem 2003 278 29655 29660 12777372 source
• Not checked yetcites [30] Brugarolas JB Vazquez F Reddy A Sellers WR Kaelin WG Jr. Cancer Cell 2003 4 147 158 12957289 source
• Not checked yetcites [31] Zundel W Genes Dev 2000 14 391 396 10691731 PMC316386 source

In the paper

“In experimental models, overexpression of HIF in tumor cells promotes metastasis”

What the sources say

• Not checked yetcites [42] Yang MH Nat. Cell Biol 2008 10 295 305 18297062 source
• Not checked yetcites [43] Hiraga T Kizaka-Kondoh S Hirota K Hiraoka M Yoneda T Cancer Res 2007 67 4157 4163 17483326 source

In the paper

“Tumor hypoxia is thought to promote the immunosuppressive phenotypes of both tumor cells and infiltrating immune cells.”

In the paper

“Together, these clinical and experimental findings demonstrate an important role for HIF signaling in metastatic tumor progression.”

In the paper

“HIF-2 expression in primary tumors is also associated with distant metastasis in patients with small cell lung and breast cancers”

What the sources say

• Not checked yetcites [39] Luan Y Pathol. Res. Pract 2013 209 184 189 23375698 source
• Not checked yetcites [40] Wang HX Qin C Han FY Wang XH Li N GMR 2014 13 2817 2826 24535905 source

In the paper

“Immunohistochemical analysis of human primary tumor samples has revealed an association between high HIF-1 expression and metastasis in patients with gynecological, pancreatic, esophageal, lung, and prostate cancers”

What the sources say

• Not checked yetcites [36] Jin Y PLOS ONE 2015 10 e0127229 25993275 PMC4438056 source
• Not checked yetcites [37] Matsuo Y J. Hepatobiliary Pancreat. Sci 2014 21 105 112 23798470 source
• Not checked yetcites [38] Ping W Sun W Zu Y Chen W Fu X Tumour Biol 2014 35 4401 4409 24425106 source

In the paper

“Clinically, HIF-1 and HIF-2 are highly expressed in primary tumors and metastases.”

In the paper

“Moreover, increased HIF expression is often linked with increased patient mortality in a variety of human cancers”

What the sources say

• Not checked yetcites [41] Semenza GL Oncogene 2010 29 625 634 19946328 PMC2969168 source

In the paper

“whereas inactivation of HIF decreases the metastatic potential of tumor cells”

What the sources say

• Not checked yetcites [43] Hiraga T Kizaka-Kondoh S Hirota K Hiraoka M Yoneda T Cancer Res 2007 67 4157 4163 17483326 source
• Not checked yetcites [44] Wong CC Proc. Natl. Acad. Sci. U.S.A 2011 108 16369 16374 21911388 PMC3182724 source
• Not checked yetcites [45] Zhang H Oncogene 2012 31 1757 1770 21860410 PMC3223555 source
• Not checked yetcites [46] Liao D Corle C Seagroves TN Johnson RS Cancer Res 2007 67 563 572 17234764 source
• Not checked yetcites [47] Hanna SC J. Clin. Invest 2013 123 2078 2093 23563312 PMC3635738 source

In the paper

“Hypoxia and HIF promote an immunosuppressive microenvironment by recruiting regulatory T cells (Tregs), MDSCs, and macrophages into the tumor microenvironment”

What the sources say

• Not checked yetcites [57] Palazon A Goldrath AW Nizet V Johnson RS Immunity 2014 41 518 528 25367569 PMC4346319 source
• Not checked yetcites [59] Kumar V Gabrilovich DI Immunology 2014 143 512 519 25196648 PMC4253499 source

In the paper

“hypoxic tumor cells recruit myeloid cells into the tumor microenvironment through the secretion of chemokines and cytokines, including CCL5, C-X-C motif chemokine 12 (CXCL12 or SDF-1), VEGF, and endothelins”

What the sources say

• Not checked yetcites [57] Palazon A Goldrath AW Nizet V Johnson RS Immunity 2014 41 518 528 25367569 PMC4346319 source

In the paper

“Normoxic and hypoxic stabilization of HIF signaling in tumor cells promotes resistance to cytotoxic T lymphocyte–mediated lysis”

What the sources say

• Not checked yetcites [51] Lee YH Clin. Cancer Res 2015 21 1438 1446 25589622 PMC4359944 source
• Not checked yetcites [52] Noman MZ J. Immunol 2009 182 3510 3521 19265129 source
• Not checked yetcites [53] Barsoum IB Cancer Res 2011 71 7433 7441 22006996 source
• Not checked yetcites [54] Noman MZ Cancer Res 2011 71 5976 5986 21810913 source

In the paper

“Hypoxic tumor cells recruit Tregs expressing CCR10 (CC chemokine receptor type 10) and NP-1 (neuropilin-1) into the tumor microenvironment through the secretion of CCL28, transforming growth factor–beta (TGF-β), and vascular endothelial growth factor [VEGF; reviewed in (57)].”

What the sources say

• Not checked yetcites [57] Palazon A Goldrath AW Nizet V Johnson RS Immunity 2014 41 518 528 25367569 PMC4346319 source

In the paper

“hypoxic tumor cells evade innate immune recognition through the up-regulation of CD47, a cell surface molecule that interacts with signal regulatory protein alpha (SIRP α) on the surface of macrophages to block phagocytosis”

What the sources say

• Not checked yetcites [58] Zhang H Proc. Natl. Acad. Sci. U.S.A 2015 112 E6215 E6223 26512116 PMC4653179 source

In the paper

“Hypoxia promotes tumor resistance to immune attack through several HIF-dependent mechanisms.”

In the paper

“Hypoxia and HIF-mediated activation of autophagy in tumor cells also regulates natural killer (NK) cell–mediated antitumor responses; this occurs through the hypoxic degradation of NK-derived granzyme B in autophagosomes and the induction of inositol 1,4,5-trisphosphate receptor, type 1”

What the sources say

• Not checked yetcites [55] Baginska J Proc. Natl. Acad. Sci. U.S.A 2013 110 17450 17455 24101526 PMC3808626 source
• Not checked yetcites [56] Messai Y Cancer Res 2014 74 6820 6832 25297632 source

In the paper

“In vitro tumor cell migration is associated with an epithelial-mesenchymal transition (EMT).”

In the paper

“Hypoxia or overexpression of HIF is sufficient to induce EMT and invasion in multiple cell types”

What the sources say

• Not checked yetcites [42] Yang MH Nat. Cell Biol 2008 10 295 305 18297062 source
• Not checked yetcites [67] Higgins DF J. Clin. Invest 2007 117 3810 3820 18037992 PMC2082142 source
• Not checked yetcites [68] Kim WY J. Clin. Invest 2009 119 2160 2170 19662677 PMC2719950 source
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [69] Krishnamachary B Cancer Res 2003 63 1138 1143 12615733
• Not checked yetcites [70] Krishnamachary B Cancer Res 2006 66 2725 2731 16510593 source
• Not checked yetcites [71] Liu Y Tumour Biol 2014 35 8103 8114 24840636 source

In the paper

“A direct role for HIF in the regulation of key EMT transcription factors such as ZEB1, Snail, and Twist has been demonstrated through the identification of functional hypoxia response elements (HREs) within the regulatory elements of these genes”

What the sources say

• Not checked yetcites [42] Yang MH Nat. Cell Biol 2008 10 295 305 18297062 source
• Not checked yetcites [72] Luo D Wang J Li J Post M Mol. Cancer Res 2011 9 234 245 21257819 source
• Not checked yetcites [73] Zhang W PLOS ONE 2015 10 e0129603 26057751 PMC4461314 source

In the paper

“Loss of E-cadherin allows cells to detach from their neighbors and begin their migratory route toward the circulatory or lymphatic system to seek out new terrain.”

In the paper

“hypoxia inhibits the effector functions of tumor-infiltrating lymphocytes largely through the accumulation of extracellular adenosine”

What the sources say

• Not checked yetcites [59] Kumar V Gabrilovich DI Immunology 2014 143 512 519 25196648 PMC4253499 source

In the paper

“work with experimental models has demonstrated that loss of E-cadherin is sufficient to promote metastasis of malignant cells”

What the sources say

• Not checked yetcites [66] Derksen PW Cancer Cell 2006 10 437 449 17097565 source

In the paper

“Collectively, these findings illustrate the diverse ways in which HIF signaling within tumor cells, MDSCs, and tumor-associated macrophages help establish an immunosuppressive tumor microenvironment.”

In the paper

“Reduced expression of E-cadherin is often observed in metastatic tumors”

In the paper

“Adenosine signals through A2A receptors on T cells to increase cyclic adenosine 3′,5′-monophosphate, which inhibits T cell proliferation, expansion, and cytokine secretion”

What the sources say

• Not checked yetcites [59] Kumar V Gabrilovich DI Immunology 2014 143 512 519 25196648 PMC4253499 source

In the paper

“We recently identified the AXL receptor tyrosine kinase as a novel HIF target driving EMT, invasion, and metastasis in VHL-deficient and hypoxic cancer cells”

What the sources say

• Not checked yetcites [80] Rankin EB Proc. Natl. Acad. Sci. U.S.A 2014 111 13373 13378 25187556 PMC4169907 source

In the paper

“AXL inhibition has been reported to sensitize drug-resistant mesenchymal tumor cells to anticancer agents, including antimitotic agents, epidermal growth factor receptor (EGFR) inhibitors, and PI3K inhibitors”

What the sources say

• Not checked yetcites [83] Byers LA Clin. Cancer Res 2013 19 279 290 23091115 PMC3567921 source
• Not checked yetcites [84] Zhang Z Nat. Genet 2012 44 852 860 22751098 PMC3408577 source
• Not checked yetcites [85] Elkabets M Cancer Cell 2015 27 533 546 25873175 PMC4398915 source
• Not checked yetcites [86] Wilson C Cancer Res 2014 74 5878 5890 25125659 source

In the paper

“The HIF pathway also indirectly promotes EMT through a number of cell signaling pathways, including Notch (74, 75), TGF-β (76), integrin-linked kinase (77), certain tyrosine kinase receptors (48), Wnt (73), and Hedgehog (78, 79).”

What the sources say

• Not checked yetcites [74] Chen J Imanaka N Chen J Griffin JD Br. J. Cancer 2010 102 351 360 20010940 PMC2816657 source
• Not checked yetcites [75] Sahlgren C Gustafsson MV Jin S Poellinger L Lendahl U Proc. Natl. Acad. Sci. U.S.A 2008 105 6392 6397 18427106 PMC2359811 source
• Not checked yetcites [76] Copple BL Liver Int 2010 30 669 682 20158611 PMC3111074 source
• Not checked yetcites [77] Chou CC Chuang HC Salunke SB Kulp SK Chen CS Oncotarget 2015 6 8271 8285 25821081 PMC4480751 source

In the paper

“A growing body of literature supports an essential role for AXL in promoting metastasis within many tumor types, including breast (81), ovarian (82), and lung (83).”

What the sources say

• Not checked yetcites [81] Gjerdrum C Proc. Natl. Acad. Sci. U.S.A 2010 107 1124 1129 20080645 PMC2824310 source
• Not checked yetcites [82] Rankin EB Cancer Res 2010 70 7570 7579 20858715 PMC3408227 source
• Not checked yetcites [83] Byers LA Clin. Cancer Res 2013 19 279 290 23091115 PMC3567921 source

In the paper

“The BMDCs promote metastasis by producing chemokines that recruit tumor cells to the lung by mechanisms that include stimulation of tumor cell extravasation”

What the sources say

• Not checked yetcites [44] Wong CC Proc. Natl. Acad. Sci. U.S.A 2011 108 16369 16374 21911388 PMC3182724 source
• Not checked yetcites [90] Kaplan RN Nature 2005 438 820 827 16341007 PMC2945882 source
• Not checked yetcites [91] Erler JT Nature 2006 440 1222 1226 16642001 source
• Not checked yetcites [92] Erler JT Cancer Cell 2009 15 35 44 19111879 PMC3050620 source
• Not checked yetcites [93] Yang L Cancer Cell 2004 6 409 421 15488763 source
• Not checked yetcites [94] Lyden D Nat. Med 2001 7 1194 1201 11689883 source
• Not checked yetcites [95] Gao D Science 2008 319 195 198 18187653 source

In the paper

“HIF signaling in the primary tumor contributes to the production of secreted factors involved in premetastatic niche formation”

In the paper

“experiments in mice have convincingly shown that formation of a tumor-promoting premetastatic niche in secondary organs is essential for the extravasation and growth of metastatic tumor cells at the distant site”

What the sources say

• Not checked yetcites [90] Kaplan RN Nature 2005 438 820 827 16341007 PMC2945882 source

In the paper

“In breast cancer cells, HIF signaling results in the increased expression and secretion of lysyl oxidase (LOX) and LOX-like proteins (LOXL2 and 4).”

In the paper

“AXL thus appears to be a promising therapeutic target for the treatment of advanced cancer”

In the paper

“These proteins modify the collagen matrix in the lung to recruit bone marrow–derived cells (BMDCs) that prime the lung for metastatic colonization.”

In the paper

“The finding that the premetastatic niche is in part established by tumor-secreted factors has stimulated great interest”

In the paper

“These findings suggest that LOX may be an important biomarker to identify ER− negative patients who are at risk for bone relapse.”

In the paper

“high expression of LOX in primary tumors was found to be associated with the formation of osteolytic bone lesions in mice”

• Also stated in: § HIF signaling and the premetastatic niche · plain

  “and high expression of LOX in primary tumors was found to be associated with the formation of osteolytic bone lesions in mice (96).”

What the sources say

• Not checked yetcites [96] Cox TR Nature 2015 522 106 110 26017313 PMC4961239 source

In the paper

“Recent studies have shown that LOX is also a key factor in the establishment of the premetastatic niche in bone.”

In the paper

“Additionally, LOX expression is clinically associated with estrogen receptor negative (ER−) breast cancer metastasis to bone.”

What the sources say

• Not checked yetcites [96] Cox TR Nature 2015 522 106 110 26017313 PMC4961239 source

In the paper

“In preclinical models, LOX expression in MDA-231 bone-tropic cells within the primary tumor is both necessary and sufficient to induce osteolytic bone lesions and cortical bone loss in immunocompromised mice even before the arrival of tumor cells.”

What the sources say

• Not checked yetcites [96] Cox TR Nature 2015 522 106 110 26017313 PMC4961239 source

In the paper

“Proteomic analysis of the hypoxic secretome in bone tropic MDA-231 human breast cancer cells compared to MDA-231 parental cells identified LOX as one of the most highly up-regulated secreted proteins in bone-tropic cells”

What the sources say

• Not checked yetcites [96] Cox TR Nature 2015 522 106 110 26017313 PMC4961239 source

In the paper

“Interestingly, IL-6–induced VEGF expression in LECs is associated with the activation of HIF-1”

What the sources say

• Not checked yetcites [98] Lee E Nat. Commun 2014 5 4715 25178650 PMC4351998 source

In the paper

“Lymphatic vessels at the distant site support metastatic colonization in breast, melanoma, prostate, gastric, and colon cancer patients (98).”

What the sources say

• Not checked yetcites [98] Lee E Nat. Commun 2014 5 4715 25178650 PMC4351998 source

In the paper

“LECs within premetastatic organs are conditioned by tumor-derived factors to facilitate tumor cell recruitment, extravasation, and colonization (98).”

What the sources say

• Not checked yetcites [98] Lee E Nat. Commun 2014 5 4715 25178650 PMC4351998 source

In the paper

“LECs accomplish this by producing chemoattractants, including SDF-1 and CCL21, that bind to cognate receptors CXCR4 and CCR7, respectively, which are expressed by tumor cells (99).”

What the sources say

• Not checked yetcites [99] Albrecht I Christofori G Int. J. Dev. Biol 2011 55 483 494 21858772 source

In the paper

“Another mechanism by which breast cancer cells condition the premetastatic niche is through tumor-lymphatic vessel cross-talk.”

What the sources say

• Not checked yetcites [98] Lee E Nat. Commun 2014 5 4715 25178650 PMC4351998 source

In the paper

“Lymphatic endothelial cells (LECs) are a specialized endothelium that line lymphatic vessels and promote lymph metastases by actively recruiting tumor cells to the lymphatic vessels.”

What the sources say

• Not checked yetcites [99] Albrecht I Christofori G Int. J. Dev. Biol 2011 55 483 494 21858772 source

In the paper

“Collectively, these studies demonstrate that hypoxia and HIF signaling mediates tumor-stromal cross-talk by activating the expression of circulating factors that can prime and direct metastatic growth.”

In the paper

“This work suggests that hypoxia can influence exosome cargo content to promote angiogenesis.”

In the paper

“Interestingly, exosomes isolated from the plasma of GBM patients contain increased amounts of hypoxia-regulated proteins— including MMP9, MMP8, platelet-derived growth factor (PDGF), PAI1, and insulin-like growth factor–binding protein 3 (IGFBP3)—compared to exosomes isolated from plasma of sex- and age-matched controls (105).”

What the sources say

• Not checked yetcites [105] Kucharzewska P Proc. Natl. Acad. Sci. U.S.A 2013 110 7312 7317 23589885 PMC3645587 source

In the paper

“Additionally, these findings suggest that the hypoxic signature of exosomes may serve as a noninvasive biomarker to predict the aggressiveness of malignant tumors.”

In the paper

“indicating that tumor-derived factors may promote lymphatic metastasis at least in part through the activation of HIF signaling in LECs (98).”

What the sources say

• Not checked yetcites [98] Lee E Nat. Commun 2014 5 4715 25178650 PMC4351998 source

In the paper

“Hypoxic cells up-regulate the small guanosine triphosphatase RAB22A in a HIF-dependent manner to promote microvesicle shedding, invasion, and metastasis (106).”

What the sources say

• Not checked yetcites [106] Wang T Proc. Natl. Acad. Sci. U.S.A 2014 111 E3234 E3242 24938788 PMC4128139 source

In the paper

“Recent studies have shown that exosomes mediate hypoxia-dependent stimulation of angiogenesis in glioblastoma multiforme (GBM) through the activation of paracrine signaling in endothelial cells and pericytes (105).”

What the sources say

• Not checked yetcites [105] Kucharzewska P Proc. Natl. Acad. Sci. U.S.A 2013 110 7312 7317 23589885 PMC3645587 source

In the paper

“Using a HIF-1 transcriptional luciferase reporter mouse, they determined that colon cancer cells experience hypoxia early after hepatic dissemination.”

What the sources say

• Not checked yetcites [109] Loo JM Cell 2015 160 393 406 25601461 PMC4312495 source

In the paper

“Successful metastatic colonization requires disseminated tumor cells to adapt to the microenvironment of the distant tissue, which can be very different from that of the tissue harboring the primary tumor.”

In the paper

“Depletion of CKB increased caspase-mediated cell death in hypoxic tumor cells within the liver”

What the sources say

• Not checked yetcites [109] Loo JM Cell 2015 160 393 406 25601461 PMC4312495 source

In the paper

“CKB controls the amount of rapidly mobilized high-energy phosphates by catalyzing the transfer of a high-energy phosphate group from ATP to the metabolite creatine, producing phosphocreatine (110).”

What the sources say

• Not checked yetcites [110] Wyss M Kaddurah-Daouk R Physiol. Rev 2000 80 1107 1213 10893433 source

In the paper

““…hypoxia within the liver microenvironment selects for disseminated tumor cells that have the ability to metabolically adapt to the hypoxic stress.””

• Also stated in: § HIF signaling and cellular growth and survival at the distant site · boosted

  “Thus, these studies demonstrate that hypoxia within the liver microenvironment selects for disseminated tumor cells that have the ability to metabolically adapt to the hypoxic stress.”

In the paper

“Under conditions of metabolic stress, such as hypoxia, tumor cells use phosphocreatine stores as a source of high-energy phosphate that can be transferred to adenosine 5′-diphosphate (ADP) to generate ATP (110).”

What the sources say

• Not checked yetcites [110] Wyss M Kaddurah-Daouk R Physiol. Rev 2000 80 1107 1213 10893433 source

In the paper

“They found that the disseminated cancer cells increase their release of the enzyme creatine kinase brain-type (CKB), which helps them survive within the hypoxic microenvironment of the liver (109).”

What the sources say

• Not checked yetcites [109] Loo JM Cell 2015 160 393 406 25601461 PMC4312495 source

In the paper

“Hypoxic stress plays an important role in immune escape by promoting immune suppression and tumor resistance.”

In the paper

“These findings suggest that breast cancer cells adapt to the hypoxic liver microenvironment through the activation of HIF signaling and glycolytic reprogramming mediated by PDK1 (Fig. 3).”

In the paper

“Finally, HIF promotes late stages of metastasis at the distant site by stimulating angiogenesis.”

In the paper

“Although hypoxia is an important factor that activates HIF signaling within tumors, recent studies have demonstrated that malignant cells use multiple strategies to enhance HIF signaling during progression by promoting HIF-α mRNA translation, protein stability, and downstream target gene expression.”

In the paper

“The hypoxic tumor microenvironment influences both the early and late stages of metastasis.”

In the paper

“Notably, PDK1 expression was elevated in breast cancer liver metastases compared to primary tumor specimens, further supporting the notion that PDK1 expression is particularly important for the growth and survival of breast cancer cells within the liver microenvironment.”

What the sources say

• Not checked yetcites [111] Dupuy F Cell Metab 2015 22 577 589 26365179 source

In the paper

“Like primary tumors, metastases require angiogenesis to support their growth.”

In the paper

“The metabolic reprogramming of liver-metastatic breast cancer cells was largely dependent on the HIF-1 target gene pyruvate dehydrogenase kinase (PDK1).”

What the sources say

• Not checked yetcites [111] Dupuy F Cell Metab 2015 22 577 589 26365179 source

In the paper

“Hypoxia and HIF-dependent signaling play an important role in metastatic tumor progression.”

In the paper

“PDK1 represses mitochondrial function by antagonizing the function of pyruvate dehydrogenase (PDH), a rate-limiting enzyme for pyruvate conversion to acetyl–coenzyme A and entry into the tricarboxylic acid cycle (112).”

What the sources say

• Not checked yetcites [112] Papandreou I Cairns RA Fontana L Lim AL Denko NC Cell Metab 2006 3 187 197 16517406 source

In the paper

“Consistent with the concept that hepatic hypoxia and the associated glycolytic phenotype in periportal regions of the liver provide a barrier for metastatic colonization, Dupuy and colleagues observed that breast metastases to the liver are highly dependent on glycolysis for survival in comparison to bone and lung metastases (111).”

What the sources say

• Not checked yetcites [111] Dupuy F Cell Metab 2015 22 577 589 26365179 source

In the paper

“As a result, a number of new biomarkers and therapeutic targets have been identified that could potentially be valuable for the detection and treatment of metastatic disease.”

In the paper

“Additionally, colon cancer cells adapt to the metabolic stress within the hypoxic liver by releasing CKB into the extracellular space to generate and import phosphocreatine as a source of ATP generation in this microenvironment.”

In the paper

“In addition, HIF signaling promotes the production of secreted factors such as LOX, LOX-like proteins, and exosomes to establish a prometastatic environment within the lung and bones of breast cancer patients.”

In the paper

“Hypoxia at the distant site also plays a substantial role in selecting for metastatic cells that can survive the metabolic stress associated with hypoxia.”

In the paper

“Metastatic breast cancer cells activate HIF signaling within the hypoxic environment of the liver to metabolically adapt to the glycolytic environment.”

In the paper

“Within the primary tumor, HIF-dependent gene expression controls EMT, invasion, migration, and angiogenesis to support the early stages of metastasis.”