Receptor Tyrosine Kinases and TLR/IL1Rs Unexpectedly Activate Myeloid Cell PI3Kγ, A Single Convergent Point Promoting Tumor Inflammation and Progression
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Tumor inflammation promotes angiogenesis, immunosuppression, and tumor growth, but the mechanisms controlling inflammatory cell recruitment to tumors are not well understood. We found that a range of chemoattractants activating G protein-coupled receptors (GPCRs), receptor tyrosine kinases (RTKs) and Toll-like/IL-1 receptors (TLR/IL1Rs) unexpectedly initiate tumor inflammation by activating the PI3-kinase isoform p110γ in Gr1+CD11b+ myeloid cells. Whereas GPCRs activate p110γ in a Ras/p101-dependent manner, RTKs and TLR/IL1Rs directly activate p110γ in a Ras/p87-dependent manner. Once activated, p110γ promotes inside-out activation of a single integrin, α4β1, causing myeloid cell invasion into tumors. Pharmacological or genetic blockade of p110γ suppressed inflammation, growth, and metastasis of implanted and spontaneous tumors, revealing an important therapeutic target in oncology.
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α4β1/αvβ3 integrins are expressed in hematopoietic and endothelial cells and play a key role in inflammation.
“The α4β1/αvβ3 integrins are expressed in hematopoietic and endothelial cells [14] and play a key role in inflammation [15], [29], [46], [47].”
From Rac2 Controls Tumor Growth, Metastasis and M1-M2 Macrophage Differentiation In Vivo (2014) · cites this paper as [29]
The Introduction states that integrins play key roles in inflammation, and the Results identify α4β1 as important for myeloid-cell trafficking to tumors. The paper does not establish the same inflammatory role for αvβ3; in the Results, inhibiting αvβ3 had no effect on the myeloid-cell adhesion tested. The expression claim has a separate citation in the citing sentence. (LLM, conf=0.85)
Experimental — accuracy not yet measuredα4β1 is involved in tumor progression involving the TLR4 signaling pathway and p110γ axis.
“Other investigators have shown that α4β1 is involved in tumor progression involving the TLR4 signaling pathway and p110γ axis.”
From Rac2 Controls Tumor Growth, Metastasis and M1-M2 Macrophage Differentiation In Vivo (2014) · cites this paper as [29]
The Discussion states that TLR/IL1R signaling activates p110γ, which promotes α4β1 activation and tumor progression; the Results also link p110γ-mediated α4β1 activation to tumor growth. Our copy does not identify TLR4 specifically, so the claim's narrower receptor attribution is not established. (LLM, conf=0.85)
Experimental — accuracy not yet measuredα4Y991A knock-in mice display a defect in macrophage entry into the tumor microenvironment, whereas Rac2-/- mice do not.
“As expected, our data demonstrate that the phenotype of the α4Y991A knock-in differs significantly from the Rac2 -/- mice in that α4Y991A knock-in mice as reported by Schmidt et al [29] display a defect in Mθ entry into the TME whereas no such defect is noted in Rac2-/- mice.”
From Rac2 Controls Tumor Growth, Metastasis and M1-M2 Macrophage Differentiation In Vivo (2014) · cites this paper as [29]
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Cites
Immunity, Inflammation, and Cancer
Grivennikov, S. I., Greten, F. R., & Karin, M. (2010) · Cell · doi:10.1016/j.cell.2010.01.025 · Cited by 10,755 · see citing works
Myeloid-derived-suppressor cells as regulators of the immune system
Gabrilovich, D. I., & Nagaraj, S. (2009) · Nature Reviews Immunology · doi:10.1038/nri2506 · Cited by 6,753 · see citing works
Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm
Biswas, S. K., & Mantovani, A. (2010) · Nature Immunology · doi:10.1038/ni.1937 · Cited by 3,840 · see citing works
Polarization of Tumor-Associated Neutrophil Phenotype by TGF-β: “N1” versus “N2” TAN
Fridlender, Z. G., Sun, J., Kim, S., Kapoor, V., Cheng, G., Ling, L. E., Worthen, G. S., & Albelda, S. Μ. (2009) · Cancer Cell · doi:10.1016/j.ccr.2009.06.017 · Cited by 3,382 · see citing works
The emerging mechanisms of isoform-specific PI3K signalling
Vanhaesebroeck, B., Guillermet-Guibert, J., Graupera, M., & Bilanges, B. (2010) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2882 · Cited by 1,767 · see citing works
De Palma, M., Venneri, M. A., Galli, R., Sergi, L. S., Politi, L. S., Sampaolesi, M., & Naldini, L. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.08.002 · Cited by 1,311 · see citing works
Central Role for G Protein-Coupled Phosphoinositide 3-Kinase γ in Inflammation
Hirsch, E., Katanaev, V. L., Garlanda, C., Azzolino, O., Pirola, L., Silengo, L., Sozzani, S., Mantovani, A., Altruda, F., & Wymann, M. P. (2000) · Science · doi:10.1126/science.287.5455.1049 · Cited by 1,209 · see citing works
Self-citationYang, L., DeBusk, L. M., Fukuda, K., Fingleton, B., Green-Jarvis, B., Shyr, Y., Matrisian, L. M., Carbone, D. P., & Lin, P. C. (2004) · Cancer Cell · doi:10.1016/j.ccr.2004.08.031 · Cited by 1,140 · see citing works
Du, R., Lu, K. V., Petritsch, C. K., Liu, P., Ganß, R., Passegue, E. A., Song, H., VandenBerg, S. R., Johnson, R. S., Werb, Z., et al. (2008) · Cancer Cell · doi:10.1016/j.ccr.2008.01.034 · Cited by 1,131 · see citing works
VEGF-Induced Adult Neovascularization: Recruitment, Retention, and Role of Accessory Cells
Grunewald, M., Avraham, I., Dor, Y., Bachar-Lustig, E., Itin, A., Yung, S., Chimenti, S., Landsman, L., Abramovitch, R., & Keshet, E. (2006) · Cell · doi:10.1016/j.cell.2005.10.036 · Cited by 1,125 · see citing works
Carcinoma-produced factors activate myeloid cells through TLR2 to stimulate metastasis
Kim, S., Takahashi, H., Lin, W.-W., Descargues, P., Grivennikov, S., Kim, Y., Luo, J.-L., & Karin, M. (2009) · Nature · doi:10.1038/nature07623 · Cited by 1,100 · see citing works
Macrophages Regulate the Angiogenic Switch in a Mouse Model of Breast Cancer
Lin, E. Y., Li, J.-F., Gnatovskiy, L., Deng, Y., Zhu, L., Grzesik, D. A., Qian, H., Xue, X.-N., & Pollard, J. W. (2006) · Cancer Research · doi:10.1158/0008-5472.can-06-1278 · Cited by 1,074 · see citing works
Function of PI3Kγ in Thymocyte Development, T Cell Activation, and Neutrophil Migration
Sasaki, T., Irie-Sasaki, J., Jones, R. G., Oliveira-dos-Santos, A., Stanford, W. L., Bolon, B. N., Wakeham, A. C., Itié, A., Bouchard, D., Kozieradzki, I., et al. (2000) · Science · doi:10.1126/science.287.5455.1040 · Cited by 1,027 · see citing works
TGF-β and immune cells: an important regulatory axis in the tumor microenvironment and progression
Yang, L., Pang, Y., & Moses, H. L. (2010) · Trends in Immunology · doi:10.1016/j.it.2010.04.002 · Cited by 1,023 · see citing works
Roles of PLC-β2 and -β3 and PI3Kγ in Chemoattractant-Mediated Signal Transduction
Li, Z., Jiang, H., Xie, W., Zhang, Z., Smrcka, A. V., & Wu, D. (2000) · Science · doi:10.1126/science.287.5455.1046 · Cited by 807 · see citing works
Blockade of PI3Kγ suppresses joint inflammation and damage in mouse models of rheumatoid arthritis
Camps, M., Rückle, T., Ji, H., Ardissone, V., Rintelen, F., Shaw, J. P., Ferrandi, C., Chabert, C., Gilliéron, C., Françon, B., et al. (2005) · Nature Medicine · doi:10.1038/nm1284 · Cited by 753 · see citing works
Self-citationChemokines and chemokine receptors: new insights into cancer-related inflammation
Lazennec, G., & Richmond, A. J. (2010) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2010.01.003 · Cited by 651 · see citing works
Bv8 regulates myeloid-cell-dependent tumour angiogenesis
Shojaei, F., Wu, X., Zhong, C., Yu, L., Liang, X., Yao, J. J., Blanchard, D., Bais, C., Peale, F. V., Jr., van Bruggen, N., et al. (2007) · Nature · doi:10.1038/nature06348 · Cited by 640 · see citing works
Crystal Structure and Functional Analysis of Ras Binding to Its Effector Phosphoinositide 3-Kinase γ
Pacold, M. E., Suire, S., Perišić, O., Lara‐González, S., Davis, C. T., Walker, E. H., Hawkins, P. T., Stephens, L., Eccleston, J. F., & Williams, R. L. (2000) · Cell · doi:10.1016/s0092-8674(00)00196-3 · Cited by 603 · see citing works
INTEGRIN STRUCTURE, ALLOSTERY, AND BIDIRECTIONAL SIGNALING
Arnaout, M. A., Mahalingam, B., & Xiong, J.-P. (2005) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.21.090704.151217 · Cited by 551 · see citing works
Inflammation Induces Myeloid-Derived Suppressor Cells that Facilitate Tumor Progression
Bunt, S. K., Sinha, P., Clements, V. K., Leips, J., & Ostrand‐Rosenberg, S. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.176.1.284 · Cited by 539 · see citing works
Bronte, V., Apolloni, E., Cabrelle, A., Ronca, R., Serafini, P., Zamboni, P., Restifo, N. P., & Zanovello, P. (2000) · Blood · doi:10.1182/blood.v96.12.3838 · Cited by 527 · see citing works
Interactions between lymphocytes and myeloid cells regulate pro- versus anti-tumor immunity
DeNardo, D. G., Andreu, P., & Coussens, L. M. (2010) · Cancer and Metastasis Reviews · doi:10.1007/s10555-010-9223-6 · Cited by 513 · see citing works
Patrucco, E., Notte, A., Barberis, L., Selvetella, G., Maffei, A., Brancaccio, M., Marengo, S., Russo, G., Azzolino, O., Rybalkin, S. D., et al. (2004) · Cell · doi:10.1016/j.cell.2004.07.017 · Cited by 465 · see citing works
Self-citationCarpenter, C. L., Auger, K. R., Chanudhuri, M., Yoakim, M., Schaffhausen, B. S., Shoelson, S. E., & Cantley, L. C. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)98375-4 · Cited by 388 · see citing works
The pathophysiologic role of alpha 4 integrins in vivo.
Lobb, R. R., & Hemler, M. E. (1994) · Journal of Clinical Investigation · doi:10.1172/jci117519 · Cited by 378 · see citing works
RIAM Activates Integrins by Linking Talin to Ras GTPase Membrane-targeting Sequences
Lee, H. S., Lim, C. J., Puzon-McLaughlin, W., Shattil, S. J., & Ginsberg, M. H. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m807117200 · Cited by 319 · see citing works
Self-citationScott, L. M., Priestley, G. V., & Papayannopoulou, T. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.24.9349-9360.2003 · Cited by 301 · see citing works
Luque, A., Gómez, M., Puzon-McLaughlin, W., Takada, Y., Sánchez‐Madrid, F., & Cabañas, C. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.19.11067 · Cited by 296 · see citing works
Integrin modulation and signaling in leukocyte adhesion and migration
Rose, D. M., Alon, R., & Ginsberg, M. H. (2007) · Immunological Reviews · doi:10.1111/j.1600-065x.2007.00536.x · Cited by 243 · see citing works
Self-citationBergmeier, W., Goerge, T., Wang, H., Crittenden, J. R., Baldwin, A. C. W., Cifuni, S. M., Housman, D. E., Graybiel, A. M., & Wagner, D. D. (2007) · Journal of Clinical Investigation · doi:10.1172/jci30575 · Cited by 190 · see citing works
Assembly and Trafficking of Heterotrimeric G Proteins
Marrari, Y., Crouthamel, M., Irannejad, R., & Wedegaertner, P. (2007) · Biochemistry · doi:10.1021/bi700338m · Cited by 176 · see citing works
Luo, J., Field, S. J., Lee, J. Y., Engelman, J. A., & Cantley, L. C. (2005) · The Journal of Cell Biology · doi:10.1083/jcb.200503088 · Cited by 172 · see citing works
Self-citationSuire, S., Condliffe, A. M., Ferguson, G., Ellson, C. D., Guillou, H., Davidson, K., Welch, H. C. E., Coadwell, J., Turner, M., Chilvers, E. R., et al. (2006) · Nature Cell Biology · doi:10.1038/ncb1494 · Cited by 168 · see citing works
Role of myeloid cells in vascular endothelial growth factor-independent tumor angiogenesis
Ferrara, N. (2010) · Current Opinion in Hematology · doi:10.1097/moh.0b013e3283386660 · Cited by 139 · see citing works
Doukas, J., Wrasidlo, W., Noronha, G., Dneprovskaia, E., Fine, R., Weis, S. M., Hood, J. D., DeMaria, A. N., Söll, R., & Cheresh, D. A. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0606956103 · Cited by 132 · see citing works
Self-citationVoigt, P., Dorner, M. B., & Schaefer, M. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m512502200 · Cited by 127 · see citing works
Integrin α4β1 Promotes Monocyte Trafficking and Angiogenesis in Tumors
Jin, H., Su, J., Garmy-Susini, B., Kleeman, J., & Varner, J. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-2704 · Cited by 127 · see citing works
Self-citationde Bruyn, K. M. T., Rangarajan, S., Reedquist, K. A., Figdor, C. G., & Bos, J. L. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m204990200 · Cited by 114 · see citing works
Ras is an indispensable coregulator of the class I B phosphoinositide 3-kinase p87/p110γ
Kurig, B., Shymanets, A., Bohnacker, T., Prajwal, P., Brock, C., Ahmadian, M. R., Schaefer, M., Gohla, A., Harteneck, C., Wymann, M. P., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0905506106 · Cited by 95 · see citing works
Interaction of Ras with phosphoinositide 3-kinase γ
Rubio, I., Rodriguez‐Viciana, P., Downward, J., & Wetzker, R. (1997) · Biochemical Journal · doi:10.1042/bj3260891 · Cited by 90 · see citing works
Serban, D., Leng, J., & Cheresh, D. A. (2008) · Circulation Research · doi:10.1161/circresaha.107.169664 · Cited by 89 · see citing works
Self-citationManevich, E., Grabovsky, V., Feigelson, S. W., & Alon, R. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m700089200 · Cited by 66 · see citing works
Development of Phosphoinositide-3 Kinase Pathway Inhibitors for Advanced Cancer
Cleary, J. M., & Shapiro, G. I. (2010) · Current Oncology Reports · doi:10.1007/s11912-010-0091-6 · Cited by 63 · see citing works
Féral, C. C. (2006) · Journal of Clinical Investigation · doi:10.1172/jci26091 · Cited by 61 · see citing works
Costa, C., Barberis, L., Ambrogio, C., Manazza, A. D., Patrucco, E., Azzolino, O., Neilsen, P. O., Ciraolo, E., Altruda, F., Prestwich, G. D., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0703175104 · Cited by 60 · see citing works
Self-citationPalanki, M. S. S., Dneprovskaia, E., Doukas, J., Fine, R., Hood, J. D., Kang, X., Lohse, D., Martin, M., Noronha, G., Söll, R., et al. (2007) · Journal of Medicinal Chemistry · doi:10.1021/jm051056c · Cited by 58 · see citing works
Self-citationZhang, X., Shephard, F., Kim, H. B., Palmer, I., McHarg, S., Fowler, G. J. S., O'Neill, L. A. J., Kiss‐Toth, E., & Qwarnström, E. E. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.073429 · Cited by 49 · see citing works
Flagged first, then by citations
1 of the 49 references couldn’t be matched to a known paper.
Research works printed but not linked: 1
- Zhang X Shephard F Kim HB Palmer IR McHarg S Fowler GJ O’Neill LA Kiss-Toth E Qwarnstrom EETIRR 2010 A novel IL1R1 co-receptor potentiates MyD88 recruitment to control Ras-dependent amplification of NF-kB J Biol Chem 285 7222 7232 19940113 PMC2844171
Cited by
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The PI3K Pathway in Human Disease
Fruman, D. A., Chiu, H., Hopkins, B. D., Bagrodia, S., Cantley, L. C., & Abraham, R. T. (2017) · Cell · doi:10.1016/j.cell.2017.07.029 · Cited by 2,749 · see citing works
PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer
Glaviano, A., Foo, A. S. C., Lam, H. Y., Yap, K. C. H., Jacot, W., Jones, R. H., Eng, H., Nair, M. G., Makvandi, P., Geoerger, B., et al. (2023) · Molecular Cancer · doi:10.1186/s12943-023-01827-6 · Cited by 2,138 · see citing works
Tumor angiogenesis: molecular pathways and therapeutic targets
Weis, S. M., & Cheresh, D. A. (2011) · Nature Medicine · doi:10.1038/nm.2537 · Cited by 1,739 · see citing works
Self-citationPI3K and cancer: lessons, challenges and opportunities
Fruman, D. A., & Rommel, C. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4204 · Cited by 1,716 · see citing works
Combining immunotherapy and targeted therapies in cancer treatment
Vanneman, M. W., & Dranoff, G. (2012) · Nature reviews. Cancer · doi:10.1038/nrc3237 · Cited by 1,583 · see citing works
PI3K in cancer: divergent roles of isoforms, modes of activation and therapeutic targeting
Thorpe, L. M., Yuzugullu, H., & Zhao, J. J. (2014) · Nature reviews. Cancer · doi:10.1038/nrc3860 · Cited by 1,365 · see citing works
PI3Kγ is a molecular switch that controls immune suppression
Kaneda, M. M., Messer, K., Ralainirina, N., Li, H., Leem, C. J., Gorjestani, S., Woo, G., Nguyen, A. V., Figueiredo, C. C., Foubert, P., et al. (2016) · Nature · doi:10.1038/nature19834 · Cited by 1,118 · see citing works
Self-citationAkt Signaling Pathway in Macrophage Activation and M1/M2 Polarization
Vergadi, E., Ieronymaki, E., Lyroni, K., Vaporidi, K., & Tsatsanis, C. (2017) · The Journal of Immunology · doi:10.4049/jimmunol.1601515 · Cited by 1,148 · see citing works
RAS-targeted therapies: is the undruggable drugged?
Moore, A. R., Rosenberg, S. C., McCormick, F., & Malek, S. (2020) · Nature Reviews Drug Discovery · doi:10.1038/s41573-020-0068-6 · Cited by 1,103 · see citing works
Huang, Y., Yuan, J., Righi, E., Kamoun, W. S., Ancukiewicz, M., Nezivar, J., Santosuosso, M., Martin, J. D., Martin, M. R., Vianello, F., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1215397109 · Cited by 1,099 · see citing works
Kinase inhibitors: the road ahead
Ferguson, F. M., & Gray, N. S. (2018) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2018.21 · Cited by 1,009 · see citing works
Cooper, J. M., & Giancotti, F. G. (2019) · Cancer Cell · doi:10.1016/j.ccell.2019.01.007 · Cited by 951 · see citing works
Targeting tumor-associated macrophages in cancer
Pathria, P., Louis, T. L., & Varner, J. A. (2019) · Trends in Immunology · doi:10.1016/j.it.2019.02.003 · Cited by 933 · see citing works
Self-citationClaesson, L., & Welsh, M. (2013) · Journal of Internal Medicine · doi:10.1111/joim.12019 · Cited by 875 · see citing works
Overcoming resistance to checkpoint blockade therapy by targeting PI3Kγ in myeloid cells
Henau, O. D., Rausch, M. P., Winkler, D. A., Campesato, L. F., Liu, C., Hirschhorn-Cymerman, D., Budhu, S., Ghosh, A., Pink, M. M., Tchaicha, J. H., et al. (2016) · Nature · doi:10.1038/nature20554 · Cited by 862 · see citing works
The complex role of tumor-infiltrating macrophages
Christofides, A., Strauss, L., Yeo, A. T., Cao, C., Charest, A., & Boussiotis, V. A. (2022) · Nature Immunology · doi:10.1038/s41590-022-01267-2 · Cited by 869 · see citing works
Wang, X., Luo, G., Zhang, K., Cao, J., Huang, C., Jiang, T., Liu, B., Su, L., & Qiu, Z. (2018) · Cancer Research · doi:10.1158/0008-5472.can-17-3841 · Cited by 768 · see citing works
The future of cancer immunotherapy: microenvironment-targeting combinations
Murciano‐Goroff, Y. R., Warner, A. B., & Wolchok, J. D. (2020) · Cell Research · doi:10.1038/s41422-020-0337-2 · Cited by 753 · see citing works
Metabolic Reprogramming of Immune Cells in Cancer Progression
Biswas, S. K. (2015) · Immunity · doi:10.1016/j.immuni.2015.09.001 · Cited by 713 · see citing works
Kim, K., Skora, A. D., Li, Z., Liu, Q., Tam, A. J., Blosser, R. L., Diaz, L. A., Papadopoulos, N., Kinzler, K. W., Vogelstein, B., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1410626111 · Cited by 676 · see citing works
Inactivation of PI(3)K p110δ breaks regulatory T-cell-mediated immune tolerance to cancer
Ali, K., Soond, D. R., Piñeiro, R., Hagemann, T., Pearce, W. P., Lim, E. L., Bouabe, H., Scudamore, C. L., Hancox, T. C., Maecker, H. L., et al. (2014) · Nature · doi:10.1038/nature13444 · Cited by 530 · see citing works
Myeloid immunosuppression and immune checkpoints in the tumor microenvironment
Nakamura, K., & Smyth, M. J. (2019) · Cellular and Molecular Immunology · doi:10.1038/s41423-019-0306-1 · Cited by 521 · see citing works
Bruton Tyrosine Kinase–Dependent Immune Cell Cross-talk Drives Pancreas Cancer
Gunderson, A. J., Kaneda, M. M., Tsujikawa, T., Nguyen, A. V., Affara, N. I., Ruffell, B., Gorjestani, S., Liudahl, S. M., Truitt, M., Olson, P., et al. (2015) · Cancer Discovery · doi:10.1158/2159-8290.cd-15-0827 · Cited by 485 · see citing works
Self-citationBig opportunities for small molecules in immuno-oncology
Adams, J. L., Smothers, J. F., Srinivasan, R., & Hoos, A. (2015) · Nature Reviews Drug Discovery · doi:10.1038/nrd4596 · Cited by 482 · see citing works
Immune Checkpoint Inhibitors: Basics and Challenges
Li, B., Chan, H. L., & Chen, P. (2017) · Current Medicinal Chemistry · doi:10.2174/0929867324666170804143706 · Cited by 473 · see citing works
Macrophage-secreted granulin supports pancreatic cancer metastasis by inducing liver fibrosis
Nielsen, S. R., Quaranta, V., Linford, A., Emeagi, P., Rainer, C., Santos, A., Ireland, L., Sakai, T., Sakai, K., Kim, Y.-S., et al. (2016) · Nature Cell Biology · doi:10.1038/ncb3340 · Cited by 441 · see citing works
Self-citationUnravelling the complexity of metastasis — molecular understanding and targeted therapies
Sethi, N. S., & Kang, Y. (2011) · Nature reviews. Cancer · doi:10.1038/nrc3125 · Cited by 396 · see citing works
Christoffersson, G., Vågesjö, E., Vandooren, J., Lidén, M., Massena, S., Reinert, R. B., Briššová, M., Powers, A. C., Opdenakker, G., & Phillipson, M. (2012) · Blood · doi:10.1182/blood-2012-04-421040 · Cited by 384 · see citing works
PI3K-AKT-mTOR inhibition in cancer immunotherapy, redux
O’Donnell, J. S., Massi, D., Teng, M. W. L., & Mandalà, M. (2017) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2017.04.015 · Cited by 382 · see citing works
The phase 3 DUO trial: duvelisib vs ofatumumab in relapsed and refractory CLL/SLL
Flinn, I. W., Hillmen, P., Montillo, M., Nagy, Z., Illés, Á., Étienne, G., Delgado, J., Kuss, B. J., Tam, C. S. L., Gasztonyi, Z., et al. (2018) · Blood · doi:10.1182/blood-2018-05-850461 · Cited by 342 · see citing works
Macrophage PI3Kγ Drives Pancreatic Ductal Adenocarcinoma Progression
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Role of the tumor microenvironment in tumor progression and the clinical applications (Review)
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Anfray, C., Ummarino, A., Andón, F. T., & Allavena, P. (2019) · Cells · doi:10.3390/cells9010046 · Cited by 275 · see citing works
Integrin CD11b activation drives anti-tumor innate immunity
Schmid, M. C., Khan, S. Q., Kaneda, M. M., Pathria, P., Shepard, R. M., Louis, T. L., Anand, S., Woo, G., Leem, C. J., Faridi, M. H., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-07387-4 · Cited by 303 · see citing works
Self-citationTargeting Interleukin-1 in Heart Disease
Tassell, B. W. V., Toldo, S. A., Mezzaroma, E., & Abbate, A. (2013) · Circulation · doi:10.1161/circulationaha.113.003199 · Cited by 306 · see citing works
Macrophages as Key Drivers of Cancer Progression and Metastasis
Nielsen, S. R., & Schmid, M. C. (2017) · Mediators of Inflammation · doi:10.1155/2017/9624760 · Cited by 281 · see citing works
Self-citationMacrophages: The Road Less Traveled, Changing Anticancer Therapy
Guerriero, J. L. (2018) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2018.03.006 · Cited by 293 · see citing works
Spranger, S. (2016) · International Immunology · doi:10.1093/intimm/dxw014 · Cited by 292 · see citing works
Horwitz, S. M., Koch, R., Porcu, P., Oki, Y., Moskowitz, A., Perez, M., Myskowski, P., Officer, A., Jaffe, J. D., Morrow, S. N., et al. (2018) · Blood · doi:10.1182/blood-2017-08-802470 · Cited by 290 · see citing works
PI3K inhibitors in inflammation, autoimmunity and cancer
Stark, A., Sriskantharajah, S., Hessel, E., & Okkenhaug, K. (2015) · Current opinion in pharmacology (Print) · doi:10.1016/j.coph.2015.05.017 · Cited by 266 · see citing works
Angiogenesis in pancreatic cancer: current research status and clinical implications
Li, S., Xu, H., Wu, C., Wang, W.-Q., Jin, W., Gao, H.-L., Li, H., Zhang, S.-R., Xu, J.-Z., Qi, Z.-H., et al. (2018) · Angiogenesis · doi:10.1007/s10456-018-9645-2 · Cited by 285 · see citing works
Mitroulis, I., Alexaki, V. I., Kourtzelis, I., Ziogas, A., Hajishengallis, G., & Chavakis, T. (2014) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2014.11.008 · Cited by 281 · see citing works
Metabolic reprogramming of macrophages during infections and cancer
Wang, S., Liu, R., Yu, Q., Dong, L., Bi, Y., & Liu, G. (2019) · Cancer Letters · doi:10.1016/j.canlet.2019.03.015 · Cited by 271 · see citing works
Okkenhaug, K., Graupera, M., & Vanhaesebroeck, B. (2016) · Cancer Discovery · doi:10.1158/2159-8290.cd-16-0716 · Cited by 264 · see citing works
Winkler, D. G., Faia, K. L., DiNitto, J. P., Ali, J. A., White, K., Brophy, E. E., Pink, M. M., Proctor, J., Lussier, J., Martin, C. M., et al. (2013) · Chemistry & Biology · doi:10.1016/j.chembiol.2013.09.017 · Cited by 262 · see citing works
Platelets: a critical link between inflammation and microvascular dysfunction
Stokes, K. Y., & Granger, D. N. (2011) · The Journal of Physiology · doi:10.1113/jphysiol.2011.225417 · Cited by 256 · see citing works
Massena, S., Christoffersson, G., Vågesjö, E., Seignez, C., Gustafsson, K. U., Binet, F., Hidalgo, C. H., Giraud, A., Lomei, J., Weström, S., et al. (2015) · Blood · doi:10.1182/blood-2015-03-631572 · Cited by 244 · see citing works
Genetically engineered T cells for cancer immunotherapy
Li, D., Li, X., Zhou, W.-L., Huang, Y., Liang, X., Jiang, L., Yang, X., Sun, J., Li, Z., Han, W., et al. (2019) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-019-0070-9 · Cited by 245 · see citing works
Chemoresistance in Pancreatic Cancer Is Driven by Stroma-Derived Insulin-Like Growth Factors
Ireland, L., Santos, A., Ahmed, M. S., Rainer, C., Nielsen, S. R., Quaranta, V., Weyer-Czernilofsky, U., Engle, D. D., Pérez-Mancera, P. A., Coupland, S. E., et al. (2016) · Cancer Research · doi:10.1158/0008-5472.can-16-1201 · Cited by 241 · see citing works
Self-citationIntegrins as attractive targets for cancer therapeutics
Li, M., Wang, Y., Li, M., Wu, X., Setrerrahmane, S., & Xu, H. (2021) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2021.01.004 · Cited by 228 · see citing works
Li, M., Li, M., Yang, Y., Liu, Y., Xie, H., Yu, Q., Tian, L., Tang, X., Ren, K., Li, J., et al. (2020) · Journal of Controlled Release · doi:10.1016/j.jconrel.2020.02.011 · Cited by 222 · see citing works
Macrophage targeting in cancer
Lopez‐Yrigoyen, M., Cassetta, L., & Pollard, J. W. (2020) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.14377 · Cited by 220 · see citing works
PI3K signalling in B- and T-lymphocytes: new developments and therapeutic advances
So, L., & Fruman, D. A. (2012) · Biochemical Journal · doi:10.1042/bj20112092 · Cited by 217 · see citing works
Synergy in activating class I PI3Ks
Burke, J. E., & Williams, R. L. (2015) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2014.12.003 · Cited by 216 · see citing works
Yang, L., Li, A., Lei, Q., & Zhang, Y. (2019) · Journal of Hematology & Oncology · doi:10.1186/s13045-019-0804-8 · Cited by 215 · see citing works
Li, M., Sala, V., Santis, M. C. D., Cimino, J. J., Cappello, P., Pianca, N., Bona, A. D., Margaria, J. P., Martini, M., Lazzarini, E., et al. (2018) · Circulation · doi:10.1161/circulationaha.117.030352 · Cited by 209 · see citing works
Self-citationCancer Vaccines, Adjuvants, and Delivery Systems
Paston, S. J., Brentville, V. A., Symonds, P., & Durrant, L. G. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.627932 · Cited by 200 · see citing works
Cancer immunotherapy: Challenges and limitations
Taefehshokr, S., Parhizkar, A., Hayati, S., Mousapour, M., Mahmoudpour, A., Eid, L. E., Rahmanpour, D., Fattahi, S., Shabani, H., & Taefehshokr, N. (2021) · Pathology - Research and Practice · doi:10.1016/j.prp.2021.153723 · Cited by 198 · see citing works
Integrins in cancer: Emerging mechanisms and therapeutic opportunities
Liu, F., Wu, Q., Dong, Z., & Liu, K. (2023) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2023.108458 · Cited by 191 · see citing works
Collagen VI in cancer and its biological mechanisms
Chen, P., Cescon, M., & Bonaldo, P. (2013) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2013.04.001 · Cited by 186 · see citing works
PI3K and Calcium Signaling in Cardiovascular Disease
Ghigo, A., Laffargue, M., Li, M., & Hirsch, E. (2017) · Circulation Research · doi:10.1161/circresaha.117.310183 · Cited by 186 · see citing works
Self-citationMetabolic Reprogramming Induces Macrophage Polarization in the Tumor Microenvironment
Wang, S., Liu, G., Li, Y., & Pan, Y. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.840029 · Cited by 194 · see citing works
Balakrishnan, K., Peluso, M., Fu, M., Rosin, N. Y., Burger, J. A., Wierda, W. G., Keating, M. J., Faia, K., O'Brien, S. M., Kutok, J. L., et al. (2015) · Leukemia · doi:10.1038/leu.2015.105 · Cited by 166 · see citing works
Targeting cancer‐related inflammation in the era of immunotherapy
Nakamura, K., & Smyth, M. J. (2016) · Immunology and Cell Biology · doi:10.1038/icb.2016.126 · Cited by 163 · see citing works
Broek, R. V., Mohan, S., Eytan, D. F., Chen, Z., & Waes, C. V. (2013) · Oral Diseases · doi:10.1111/odi.12206 · Cited by 159 · see citing works
Intertwined regulation of angiogenesis and immunity by myeloid cells
Rivera, L. B., & Bergers, G. (2015) · Trends in Immunology · doi:10.1016/j.it.2015.02.005 · Cited by 158 · see citing works
Evans, C. A., Liu, T., Lescarbeau, A., Nair, S. J., Grenier, L., Pradeilles, J. A., Glenadel, Q., Tibbitts, T. T., Rowley, A. M., DiNitto, J. P., et al. (2016) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.6b00238 · Cited by 153 · see citing works
Small Molecules Drive Big Improvements in Immuno‐Oncology Therapies
Huck, B. R., Kötzner, L., & Urbahns, K. (2017) · Angewandte Chemie International Edition · doi:10.1002/anie.201707816 · Cited by 149 · see citing works
Intratumoral myeloid cells regulate responsiveness and resistance to antiangiogenic therapy
Rivera, L. B., Meyronet, D., Hervieu, V., Frederick, M., Bergsland, E., & Bergers, G. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.03.055 · Cited by 154 · see citing works
A selective inhibitor reveals PI3Kγ dependence of TH17 cell differentiation
Bergamini, G., Bell, K., Shimamura, S., Werner, T., Cansfield, A. D., Müller, K., Perrin, J., Rau, C., Ellard, K., Hopf, C., et al. (2012) · Nature Chemical Biology · doi:10.1038/nchembio.957 · Cited by 147 · see citing works
Self-citationMolecules in medicine mini-review: isoforms of PI3K in biology and disease
Vanhaesebroeck, B., Whitehead, M. A., & Piñeiro, R. (2015) · Journal of Molecular Medicine · doi:10.1007/s00109-015-1352-5 · Cited by 147 · see citing works
Tumor-intrinsic oncogene pathways mediating immune avoidance
Spranger, S., & Gajewski, T. F. (2015) · OncoImmunology · doi:10.1080/2162402x.2015.1086862 · Cited by 146 · see citing works
Targeting PI3K Signaling in Combination Cancer Therapy
Tostivint, E. P., Thibault, B., & Guillermet‐Guibert, J. (2017) · Trends in cancer · doi:10.1016/j.trecan.2017.04.002 · Cited by 141 · see citing works
Valilou, S. F., Keshavarz‐Fathi, M., Silvestris, N., Argentiero, A., & Rezaei, N. (2018) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2018.01.007 · Cited by 141 · see citing works
Vadas, O., Dbouk, H. A., Shymanets, A., Perišić, O., Burke, J. E., Saab, W. F. A., Khalil, B. D., Harteneck, C., Bresnick, A. R., Nürnberg, B., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1304801110 · Cited by 139 · see citing works
PI3Kδ Inhibitors in Cancer: Rationale and Serendipity Merge in the Clinic
Fruman, D. A., & Rommel, C. (2011) · Cancer Discovery · doi:10.1158/2159-8290.cd-11-0249 · Cited by 137 · see citing works
Rab8a interacts directly with PI3Kγ to modulate TLR4-driven PI3K and mTOR signalling
Luo, L., Wall, A. A., Yeo, J. C., Condon, N. D., Norwood, S. J., Schoenwaelder, S. M., Chen, K. W., Jackson, S. P., Jenkins, B. J., Hartland, E. L., et al. (2014) · Nature Communications · doi:10.1038/ncomms5407 · Cited by 136 · see citing works
Molecular Pathways: Deciphering Mechanisms of Resistance to Macrophage-Targeted Therapies
Quail, D. F., & Joyce, J. A. (2016) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-0133 · Cited by 135 · see citing works
Rathinaswamy, M. K., & Burke, J. E. (2019) · Advances in Biological Regulation · doi:10.1016/j.jbior.2019.100657 · Cited by 140 · see citing works
The therapeutic implications of immunosuppressive tumor aerobic glycolysis
Reinfeld, B. I., Rathmell, W. K., Kim, T. K., & Rathmell, J. C. (2021) · Cellular and Molecular Immunology · doi:10.1038/s41423-021-00727-3 · Cited by 131 · see citing works
Joshi, S., Singh, A. R., Zulcic, M., & Durden, D. L. (2014) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-13-0682 · Cited by 130 · see citing works
Rac2 Controls Tumor Growth, Metastasis and M1-M2 Macrophage Differentiation In Vivo
Joshi, S., Singh, A. R., Zulcic, M., Bao, L., Messer, K., Ideker, T., Dutkowski, J., & Durden, D. L. (2014) · PLoS ONE · doi:10.1371/journal.pone.0095893 · Cited by 128 · see citing works
“As expected, our data demonstrate that the phenotype of the a4Y991A knock-in differs significantly from the Rac2 -/- mice in that a4Y991A knock-in mice as reported by Schmidt et al [29] display a defect in Mh entry into the TME whereas no such defect is noted in Rac2-/- mice.”
BackgroundResultInfluentialRole of mTOR Signaling in Tumor Microenvironment: An Overview
Conciatori, F., Bazzichetto, C., Falcone, I., Pilotto, S., Bria, E., Cognetti, F., Milella, M., & Ciuffreda, L. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19082453 · Cited by 129 · see citing works
Lipid accumulation in macrophages confers protumorigenic polarization and immunity in gastric cancer
Luo, Q., Zheng, N., Jiang, L., Wang, T., Zhang, P., Liu, Y., Zheng, P., Wang, W., Xie, G., Chen, L., et al. (2020) · Cancer Science · doi:10.1111/cas.14616 · Cited by 126 · see citing works
The potential role of HIF on tumour progression and dissemination
Unwith, S., Zhao, H., Hennah, L., & Ma, D. (2014) · International Journal of Cancer · doi:10.1002/ijc.28889 · Cited by 126 · see citing works
Kim, B., Sun, S., Varner, J. A., Howell, S. B., Ruoslahti, E. I., & Sailor, M. J. (2019) · Advanced Materials · doi:10.1002/adma.201902952 · Cited by 122 · see citing works
Self-citationFoster, J. G., Blunt, M. D., Carter, E. P., & Ward, S. G. (2012) · Pharmacological Reviews · doi:10.1124/pr.110.004051 · Cited by 121 · see citing works
Joshi, S., & Durden, D. L. (2019) · Journal of Oncology · doi:10.1155/2019/5245034 · Cited by 118 · see citing works
Targeting tumor‑associated macrophages in the tumor microenvironment (Review)
Zhou, K., Cheng, T., Zhan, J., Peng, X., Zhang, Y., Wen, J., Chen, X., & Ying, M. (2020) · Oncology Letters · doi:10.3892/ol.2020.12097 · Cited by 119 · see citing works
Schmid, M. C., Avraamides, C. J., Foubert, P., Shaked, Y., Kang, S. W., Kerbel, R. S., & Varner, J. A. (2011) · Cancer Research · doi:10.1158/0008-5472.can-11-0588 · Cited by 113 · see citing works
Self-citationRecent Advancements in Nanomedicine for ‘Cold’ Tumor Immunotherapy
Chen, Q., Sun, T., & Jiang, C. (2021) · Nano-Micro Letters · doi:10.1007/s40820-021-00622-6 · Cited by 113 · see citing works
Regulation of innate immune responses by transmembrane interactions: Lessons from the TLR family
Reuven, E. M., Fink, A., & Shai, Y. (2014) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2014.01.020 · Cited by 110 · see citing works
Role of Macrophage Polarization in Tumor Angiogenesis and Vessel Normalization
Chen, P., & Bonaldo, P. (2013) · International review of cytology · doi:10.1016/b978-0-12-407704-1.00001-4 · Cited by 109 · see citing works
Heffron, T. P., Heald, R. A., Ndubaku, C. O., Wei, B. Q., Augistin, M., Do, S., Edgar, K. A., Eigenbrot, C. W., Friedman, L. S., Gancia, E., et al. (2016) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b01483 · Cited by 107 · see citing works
Poh, A. R., & Ernst, M. (2021) · Cancers · doi:10.3390/cancers13122860 · Cited by 106 · see citing works
Immune checkpoints in osteosarcoma: Recent advances and therapeutic potential
Yang, W., Tang, F., Tu, C., Hornicek, F. J., Duan, Z., & Min, L. (2022) · Cancer Letters · doi:10.1016/j.canlet.2022.215887 · Cited by 107 · see citing works
Hong, D. S., Postow, M. A., Chmielowski, B., Sullivan, R. J., Patnaik, A., Cohen, E. E. W., Shapiro, G. I., Steuer, C. E., Gutierrez, M. E., Yeckes-Rodin, H., et al. (2023) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-22-3313 · Cited by 111 · see citing works
Hurdles of CAR-T cell-based cancer immunotherapy directed against solid tumors
Zhang, B., Qin, D., Mo, Z., Li, Y., Wei, W., Wang, Y., Wang, W., & Wei, Y.-Q. (2016) · Science China Life Sciences · doi:10.1007/s11427-016-5027-4 · Cited by 105 · see citing works
Puri, K. D., & Gold, M. R. (2012) · Frontiers in Immunology · doi:10.3389/fimmu.2012.00256 · Cited by 102 · see citing works
- Authors
- Schmid, M. C., Avraamides, C. J., Dippold, H. C., Franco, I., Foubert, P., Ellies, L. G., Acevedo, L. M., Manglicmot, J. R. E., Song, X., Wrasidlo, W., Blair, S. L., Ginsberg, M. H., Cheresh, D. A., Hirsch, E., Field, S. J., & Varner, J. A.
- Affiliations
- University of California San Diego (US)
- University of Turin (IT)
- Corresponding author
- Varner, Judith A.
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2011-06
- Volume
- 19
- Issue
- 6
- Pages
- 715-727
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC3144144
- OpenAlex
- W2046905172
- Cited by
- 378
- References
- 49
- Citations by year
- 2026: 6 · 2025: 20 · 2024: 25 · 2023: 18 · 2022: 22 · 2021: 45 · 2020: 31 · 2019: 35 · 2018: 22 · 2017: 25 · 2016: 26 · 2015: 31 · 2014: 18 · 2013: 24 · 2012: 21
- FWCI
- 9.36
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 813 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Fondazione Cariplo
- Novartis
- National Institutes of Health (AR27214, DP2OD004265, HL31950, R01CA118182, R01CA126820, R01CA138676, R01CA45726, R01CA50286, R01CA83133)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- PI3Kγ, p110γ, tumor inflammation, myeloid cells, receptor tyrosine kinase, Toll-like receptors, IL-1 receptor, G protein-coupled receptors, Ras signaling, alpha4beta1 integrin, myeloid cell recruitment, metastasis, tumor growth, PI3Kγ inhibitor
- MeSH terms
- Animals, Cell Adhesion, Cell Movement, Humans, Inflammation, Mice, Inbred C57BL, Neoplasm Metastasis, Neoplasms, Receptors, Interleukin-1, Disease Progression, ras Proteins, Receptor Protein-Tyrosine Kinases, Integrin alpha4beta1, Toll-Like Receptors, Mice, Class Ib Phosphatidylinositol 3-Kinase
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