bims-stacyt Biomed news
on Paracrine crosstalk between cancer and the organism
Issue of 2019‒02‒10
seven papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge


  1. Clin Cancer Res. 2019 Feb 05. pii: clincanres.3781.2018. [Epub ahead of print]
    McGee HM, Jiang D, Soto-Pantoja DR, Nevler A, Giaccia AJ, Woodward WA.
      The development of cancers and their response to radiation are intricately linked to the tumor microenvironment in which they reside. Tumor cells, immune cells, and stromal cells interact with each other and are influenced by the microbiome and metabolic state of the host, and these interactions are constantly evolving. Stromal cells not only secrete extracellular matrix and participate in wound contraction, but they also secrete fibroblast growth factors (FGFs), which mediate macrophage differentiation. Tumor associated macrophages (TAMs) migrate to hypoxic areas and secrete VEGF to promote angiogenesis. The microbiome and its byproducts alter the metabolic milieu by shifting the balance between glucose utilization and fatty acid oxidation, and these changes subsequently influence the immune response in the tumor microenvironment (TME). Not only does radiation exert cell autonomous effects on tumor cells, but it influences both the tumor-promoting and tumor-suppressive components of the TME. To gain a deeper understanding of how the tumor microenvironment influences the response to radiation, the American Society for Radiation Oncology (ASTRO) and the American Association of Cancer Research (AACR) organized a scientific workshop on July 26-27, 2018, which focused on how the microbiome, the immune response, the metabolome, and the stroma all can shift the balance between radiosensitivity and radioresistance. The proceedings from this workshop are discussed here and highlight recent discoveries in the field as well as the most important areas for future research.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-18-3781
  2. JCI Insight. 2019 Feb 05. pii: 124989. [Epub ahead of print]
    Najjar YG, Menk AV, Sander C, Rao U, Karunamurthy A, Bhatia R, Zhai S, Kirkwood JM, Delgoffe GM.
      The tumor microenvironment presents physical, immunologic, and metabolic barriers to durable immunotherapy responses. We have recently described roles for both T cell metabolic insufficiency as well as tumor hypoxia as inhibitory mechanisms which prevent T cell activity in murine tumors, but whether intratumoral T cell activity or response to immunotherapy vary between patients as a function of distinct metabolic profiles in tumor cells remains unclear. Here we show that metabolic derangement can vary widely in both degree and type in patient-derived cell lines and in ex vivo analysis of patient samples, such that some cells demonstrate solely deregulated oxidative or glycolytic metabolism. Further, deregulated oxidative, but not glycolytic, metabolism was associated with increased generation of hypoxia upon implantation into immunodeficient animals. Generation of murine single cell melanoma cell lines that lacked either oxidative or glycolytic metabolism showed that elevated tumor oxygen consumption was associated with increased T cell exhaustion and decreased immune activity. Further, melanoma lines lacking oxidative metabolism were solely responsive to anti-PD1 therapy among those tested. Prospective analysis of patient samples immunotherapy revealed that oxidative, but not glycolytic, metabolism was associated with progression on PD-1 blockade. Our data highlight a role for oxygen as a crucial metabolite required for the tumor-infiltrating T cells to differentiate appropriately upon PD-1 blockade, and suggesting tumor oxidative metabolism may be a target to improve immunotherapeutic response.
    Keywords:  Cancer immunotherapy; Glucose metabolism; Immunology; T cells
    DOI:  https://doi.org/10.1172/jci.insight.124989
  3. Sci Signal. 2019 Feb 05. pii: eaan8247. [Epub ahead of print]12(567):
    Kugeratski FG, Atkinson SJ, Neilson LJ, Lilla S, Knight JRP, Serneels J, Juin A, Ismail S, Bryant DM, Markert EK, Machesky LM, Mazzone M, Sansom OJ, Zanivan S.
      Intratumoral hypoxia causes the formation of dysfunctional blood vessels, which contribute to tumor metastasis and reduce the efficacy of therapeutic treatments. Blood vessels are embedded in the tumor stroma of which cancer-associated fibroblasts (CAFs) constitute a prominent cellular component. We found that hypoxic human mammary CAFs promoted angiogenesis in CAF-endothelial cell cocultures in vitro. Mass spectrometry-based proteomic analysis of the CAF secretome unraveled that hypoxic CAFs contributed to blood vessel abnormalities by altering their secretion of various pro- and anti-angiogenic factors. Hypoxia induced pronounced remodeling of the CAF proteome, including proteins that have not been previously related to this process. Among those, the uncharacterized protein NCBP2-AS2 that we renamed HIAR (hypoxia-induced angiogenesis regulator) was the protein most increased in abundance in hypoxic CAFs. Silencing of HIAR abrogated the pro-angiogenic and pro-migratory function of hypoxic CAFs by decreasing secretion of the pro-angiogenic factor VEGFA and consequently reducing VEGF/VEGFR downstream signaling in the endothelial cells. Our study has identified a regulator of angiogenesis and provides a map of hypoxia-induced molecular alterations in mammary CAFs.
    DOI:  https://doi.org/10.1126/scisignal.aan8247
  4. Mol Cancer Res. 2019 Feb 04. pii: molcanres.0836.2018. [Epub ahead of print]
    Humphries BA, Buschhaus JM, Chen YC, Haley HR, Qyli T, Chiang B, Shen N, Rajendran S, Cutter A, Cheng YH, Chen YT, Cong J, Spinosa PC, Yoon E, Luker KE, Luker GD.
      Migration and invasion of cancer cells constitute fundamental processes in tumor progression and metastasis. Migratory cancer cells commonly upregulate expression of plasminogen activator inhibitor 1 (PAI1), and PAI1 correlates with poor prognosis in breast cancer. However, mechanisms by which PAI1 promotes migration of cancer cells remain incompletely defined. Here we show that increased PAI1 drives rearrangement of the actin cytoskeleton, mitochondrial fragmentation, and glycolytic metabolism in triple negative breast cancer (TNBC) cells. In two-dimensional environments, both stable expression of PAI1 and treatment with recombinant PAI1 increased migration, which could be blocked with the specific inhibitor tiplaxtinin. PAI1 also promoted invasion into the extracellular matrix from co-culture spheroids with human mammary fibroblasts in fibrin gels. Elevated cellular PAI1 enhanced cytoskeletal features associated with migration, actin-rich migratory structures and reduced actin stress fibers. In orthotopic tumor xenografts, we discovered that TNBC cells with elevated PAI1 show collagen fibers aligned perpendicular to the tumor margin, an established marker of invasive breast tumors. Further studies revealed that PAI1 activates ERK signaling, a central regulator of motility, and promotes mitochondrial fragmentation. Consistent with known effects of mitochondrial fragmentation on metabolism, fluorescence lifetime imaging microscopy (FLIM) of endogenous NADH showed that PAI1 promotes glycolysis in cell-based assays, orthotopic tumor xenografts, and lung metastases. Together, these data demonstrate for the first time that PAI1 regulates cancer cell metabolism and suggest targeting metabolism to block motility and tumor progression. Implications: We identified a novel mechanism through which cancer cells alter their metabolism to promote tumor progression.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-18-0836
  5. Int J Biochem Cell Biol. 2019 Jan 30. pii: S1357-2725(19)30023-8. [Epub ahead of print]
    Han Y, Ren J, Bai Y, Pei X, Han Y.
      BACKGROUND: We previously reported that co-transplantation of exosomes from hypoxia-preconditioned adipose mesenchymal stem cells (ADSCs) improves the neoangiogenesis and survival of the grafted tissue. This study aimed to investigate the molecular mechanism of this protective effect.METHODS: Exosomes were collected from normoxia-treated (nADSC-Exo) or hypoxia--treated (hypADSC-Exo) human ADSCs, and their pro-angiogenic capacity was evaluated in human umbilical vein endothelial cells (HUVECs) and a nude mouse model of subcutaneous fat grafting. Protein array was used to compare the exosome-derived proteins between nADSC-Exo and hypADSC-Exo.
    RESULTS: Compared with the nADSC-Exo group and untreated control, hypADSC-Exo treatment significantly promoted proliferation, migration and tube-formation capability of HUVECs. Protein array revealed that the levels of vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), fibroblast growth factor (FGF) and their receptors (VEGF-R2, VEGF-R3), and monocyte chemoattractant protein 2 (MCP-2), monocyte chemoattractant protein 4 (MCP-4) were significantly higher in the hypADSC-Exo than in the nADSC-Exo. In the nude mice model of fat grafting, immunofluorescence of CD31 showed that hypADSC-Exo dramatically improved neovascularization around the graft. Furthermore, compared with nADSC-Exo and control groups, cotransplantation of hypADSC-Exo significantly increased the protein expression of EGF, FGF, VEGF/VEGF-R, angiopoietin-1(Ang-1) and tyrosine kinase with immunoglobulin-like and EGF-like domains 1(Tie-1, an angiopoietin receptor) in the grafted tissue at 30 days after transplantation. Immunohistochemical analysis demonstrated that hypADSC-Exo treatment significantly increased VEGF-R expression in the grafted tissue.
    CONCLUSIONS: Exosomes from hypoxia-treated human ADSCs possess a higher capacity to enhance angiogenesis in fat grafting, at least partially, via regulating VEGF/VEGF-R signaling.
    Keywords:  Mesenchymal stem cells (MSCs); angiogenesis; exosomes; hypoxia; vascular endothelial growth factor (VEGF)
    DOI:  https://doi.org/10.1016/j.biocel.2019.01.017
  6. Cell. 2019 Feb 07. pii: S0092-8674(18)31652-0. [Epub ahead of print]176(4): 757-774.e23
    Georgouli M, Herraiz C, Crosas-Molist E, Fanshawe B, Maiques O, Perdrix A, Pandya P, Rodriguez-Hernandez I, Ilieva KM, Cantelli G, Karagiannis P, Mele S, Lam H, Josephs DH, Matias-Guiu X, Marti RM, Nestle FO, Orgaz JL, Malanchi I, Fruhwirth GO, Karagiannis SN, Sanz-Moreno V.
      ROCK-Myosin II drives fast rounded-amoeboid migration in cancer cells during metastatic dissemination. Analysis of human melanoma biopsies revealed that amoeboid melanoma cells with high Myosin II activity are predominant in the invasive fronts of primary tumors in proximity to CD206+CD163+ tumor-associated macrophages and vessels. Proteomic analysis shows that ROCK-Myosin II activity in amoeboid cancer cells controls an immunomodulatory secretome, enabling the recruitment of monocytes and their differentiation into tumor-promoting macrophages. Both amoeboid cancer cells and their associated macrophages support an abnormal vasculature, which ultimately facilitates tumor progression. Mechanistically, amoeboid cancer cells perpetuate their behavior via ROCK-Myosin II-driven IL-1α secretion and NF-κB activation. Using an array of tumor models, we show that high Myosin II activity in tumor cells reprograms the innate immune microenvironment to support tumor growth. We describe an unexpected role for Myosin II dynamics in cancer cells controlling myeloid function via secreted factors.
    Keywords:  NF-κB; ROCK-Myosin II; macrophages; protein secretion; rounded-amoeboid melanoma cells; tumor invasive front
    DOI:  https://doi.org/10.1016/j.cell.2018.12.038
  7. Hepatology. 2019 Feb 05.
    Wei C, Yang X, Liu N, Geng J, Tai Y, Sun Z, Mei G, Zhou P, Peng Y, Wang C, Zhang X, Zhang P, Geng Y, Wang Y, Zhang X, Liu X, Zhang Y, Wu F, He X, Zhong H.
      The unfolded protein response (UPR) signal in tumor cells activates UPR signaling in neighboring macrophages, which leads to tumor-promoting inflammation by upregulating UPR target genes and proinflammatory cytokines. However, the molecular basis of this endoplasmic reticulum (ER) stress transmission remains largely unclear. Here, we identified the secreted form of GP73, a Golgi-associated protein functional critical for hepatocellular carcinoma (HCC) growth and metastasis, is indispensable for ER stress transmission. Notably, ER stressors increased the cellular secretion of GP73. Via GRP78, the secreted GP73 stimulated ER stress activation in neighboring macrophages, which then released cytokines and chemokines involved in the tumor-associated macrophages (TAMs) phenotype. Analysis of HCC patients revealed a positive correlation of GP73 with GRP78 expression and TAMs density. High GP73 and CD206 expression was associated with poor prognosis. Blockade of GP73 decreased the density of TAMs, inhibited tumor growth and prolonged survival in two mouse HCC models. Our findings provide insight into the molecular mechanisms of extracellular GP73 in the amplification and transmission of ER stress signals. This article is protected by copyright. All rights reserved.
    DOI:  https://doi.org/10.1002/hep.30549