The DOI matches its Crossref record; 62 of the 62 references it cites were found in a registry or an index.
Metabolic Reprogramming of Stromal Fibroblasts through p62-mTORC1 Signaling Promotes Inflammation and Tumorigenesis
Open accessAbstract
The tumor microenvironment plays a critical role in cancer progression, but the precise mechanisms by which stromal cells influence the epithelium are poorly understood. Here we show that p62 levels were reduced in the stroma of several tumors and that its loss in the tumor microenvironment or stromal fibroblasts resulted in increased tumorigenesis of epithelial prostate cancer cells. The mechanism involves the regulation of cellular redox through an mTORC1/c-Myc pathway of stromal glucose and amino acid metabolism, resulting in increased stromal IL-6 production, which is required for tumor promotion in the epithelial compartment. Thus, p62 is an anti-inflammatory tumor suppressor that acts through the modulation of metabolism in the tumor stroma.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Furthermore, metabolic dysregulation of CAFs may also be coupled to altered immunoregulation, possibly through IL-6 production or depletion of immunomodulating amino acids128,132.”
From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [128]
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Hallmarks of Cancer: The Next Generation
Hanahan, D., & Weinberg, R. A. (2011) · Cell · doi:10.1016/j.cell.2011.02.013 · Cited by 66,590
Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation
Vander Heiden, M. G., Cantley, L. C., & Thompson, C. B. (2009) · Science · doi:10.1126/science.1160809 · Cited by 16,197
Coussens, L. M., & Werb, Z. (2002) · Nature · doi:10.1038/nature01322 · Cited by 15,111
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
Autophagy in the Pathogenesis of Disease
Levine, B., & Kroemer, G. (2008) · Cell · doi:10.1016/j.cell.2007.12.018 · Cited by 7,069
Accessories to the Crime: Functions of Cells Recruited to the Tumor Microenvironment
Hanahan, D., & Coussens, L. M. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.02.022 · Cited by 4,632
Dang, C. V. (2012) · Cell · doi:10.1016/j.cell.2012.03.003 · Cited by 3,390
Komatsu, M., Kurokawa, H., Waguri, S., Taguchi, K., Kobayashi, A., Ichimura, Y., Sou, Y.-S., Ueno, I., Sakamoto, A., Tong, K. I., et al. (2010) · Nature Cell Biology · doi:10.1038/ncb2021 · Cited by 2,288
Bissell, M. J., & Radisky, D. (2001) · Nature Reviews Cancer · doi:10.1038/35094059 · Cited by 2,180
Serine, glycine and one-carbon units: cancer metabolism in full circle
Locasale, J. W. (2013) · Nature reviews. Cancer · doi:10.1038/nrc3557 · Cited by 1,727
Functional genomics reveal that the serine synthesis pathway is essential in breast cancer
Possemato, R., Marks, K. M., Shaul, Y. D., Pacold, M. E., Kim, D., Birsoy, K., Sethumadhavan, S., Woo, H.-K., Jang, H. G., Jha, A. K., et al. (2011) · Nature · doi:10.1038/nature10350 · Cited by 1,683
Inflammation in prostate carcinogenesis
Marzo, A. M. D., Platz, E. A., Sutcliffe, S., Xu, J., Grönberg, H., Drake, C. G., Nakai, Y., Isaacs, W. B., & Nelson, W. G. (2007) · Nature reviews. Cancer · doi:10.1038/nrc2090 · Cited by 1,669
Inman, G. J., Nicolás, F. J., Callahan, J. F., Harling, J. D., Gaster, L. M., Reith, A. D., Laping, N. J., & Hill, C. S. (2002) · Molecular Pharmacology · doi:10.1124/mol.62.1.65 · Cited by 1,636
Gaggioli, C., Hooper, S., Hidalgo-Carcedo, C., Grosse, R., Marshall, J. F., Harrington, K., & Sahai, E. (2007) · Nature Cell Biology · doi:10.1038/ncb1658 · Cited by 1,589 · cited 2×
“p62 in Stromal Fibroblasts Regulates an IL-6/TGF-b Cascade Essential for Tumor Invasion We next set up a 3D organotypic culture model that recapitulates, in a genetically accessible system, the tumor microenvironment and its interactions with the tumor epithelial cell, closely mimicking the physiological situation and…”
BackgroundPten is essential for embryonic development and tumour suppression
Cristofano, A. D., Pesce, B., Cordon‐Cardo, C., & Pandolfi, P. P. (1998) · Nature Genetics · doi:10.1038/1235 · Cited by 1,518
Erez, N., Truitt, M., Olson, P., & Hanahan, D. (2010) · Cancer Cell · doi:10.1016/j.ccr.2009.12.041 · Cited by 1,515
Prostate cancer in a transgenic mouse.
Greenberg, N. M., DeMayo, F. J., Finegold, M. J., Medina, D., Tilley, W. D., Aspinall, J. O., Cunha, G. R., Donjacour, A. A., Matusik, R. J., & Rosen, J. M. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.8.3439 · Cited by 1,296
p62 at the crossroads of autophagy, apoptosis, and cancer
Moscat, J., & Diaz-Meco, M. T. (2009) · Cell · doi:10.1016/j.cell.2009.05.023 · Cited by 1,073
Self-citationDependency of Colorectal Cancer on a TGF-β-Driven Program in Stromal Cells for Metastasis Initiation
Calon, A., Espinet, E., Palomo-Ponce, S., Tauriello, D. V. F., Iglesias, M., Céspedes, M. V., Sevillano, M., Nadal, C., Jung, P., Zhang, X. H.-F., et al. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.08.013 · Cited by 1,060
Molecular genetics of prostate cancer: new prospects for old challengesPreprint
Shen, M. M., & Abate-Shen, C. T. (2010) · Genes & Development · doi:10.1101/gad.1965810 · Cited by 991
Cancer as an overhealing wound: an old hypothesis revisited
Schäfer, M., & Werner, S. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2455 · Cited by 974
Kojima, Y., Acar, A., Eaton, E. N., Mellody, K. T., Scheel, C., Ben‐Porath, I., Önder, T. T., Wang, Z. C., Richardson, A. L., Weinberg, R. A., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1013805107 · Cited by 894
Cellular Metabolism and Disease: What Do Metabolic Outliers Teach Us?
DeBerardinis, R. J., & Thompson, C. B. (2012) · Cell · doi:10.1016/j.cell.2012.02.032 · Cited by 858
Interleukin-6 signaling pathway in targeted therapy for cancer
Guo, Y., Xu, F., Lu, T., Duan, Z., & Zhang, Z. (2012) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2012.04.007 · Cited by 693
B-cell-derived lymphotoxin promotes castration-resistant prostate cancer
Ammirante, M., Luo, J., Grivennikov, S. I., Nedospasov, S. A., & Karin, M. (2010) · Nature · doi:10.1038/nature08782 · Cited by 651
Evidence for an Alternative Glycolytic Pathway in Rapidly Proliferating Cells
Heiden, M. G. V., Locasale, J. W., Swanson, K. D., Sharfi, H., Heffron, G. J., Amador‐Noguez, D., Christofk, H. R., Wagner, G., Rabinowitz, J. D., Asara, J. M., et al. (2010) · Science · doi:10.1126/science.1188015 · Cited by 648
Persistent activation of Nrf2 through p62 in hepatocellular carcinoma cells
Inami, Y., Waguri, S., Sakamoto, A., Kouno, T., Nakada, K., Hino, O., Watanabe, S., Ando, J., Iwadate, M., Yamamoto, M. P., et al. (2011) · The Journal of Cell Biology · doi:10.1083/jcb.201102031 · Cited by 615
Cancer-associated fibroblasts and tumor growth – bystanders turning into key players
Östman, A., & Augsten, M. (2009) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2009.01.003 · Cited by 555
The Signaling Adaptor p62 Is an Important NF-κB Mediator in Tumorigenesis
Duran, A., Linares, J. F., Galvez, A. S., Wikenheiser, K., Flores, J. M., Diaz-Meco, M. T., & Moscat, J. (2008) · Cancer Cell · doi:10.1016/j.ccr.2008.02.001 · Cited by 541
Self-citationLing, J., Kang, Y., Zhao, R., Xia, Q., Lee, D.-F., Chang, Z., Li, J., Peng, B., Fleming, J. B., Wang, H., et al. (2012) · Cancer Cell · doi:10.1016/j.ccr.2011.12.006 · Cited by 513
Pten in stromal fibroblasts suppresses mammary epithelial tumours
Trimboli, A. J., Cantemir-Stone, C. Z., Li, F., Wallace, J. A., Merchant, A. S., Creasap, N., Thompson, J. C., Caserta, E., Wang, H., Chong, J.-L., et al. (2009) · Nature · doi:10.1038/nature08486 · Cited by 507
Autophagy-Mediated Tumor Promotion
Guo, J. Y., Xia, B., & White, E. (2013) · Cell · doi:10.1016/j.cell.2013.11.019 · Cited by 506
p62 Is a Key Regulator of Nutrient Sensing in the mTORC1 Pathway
Duran, A., Amanchy, R., Linares, J. F., Joshi, J., Abu-Baker, S., Porollo, A., Hansen, M., Moscat, J., & Diaz-Meco, M. T. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.06.038 · Cited by 472
Self-citationRegulation of TFEB and V‐ATPases by mTORC1
Peña‐Llopis, S., Vega-Rubín-de-Celis, S., Schwartz, J. C., Wolff, N. C., Tran, T. A. T., Zou, L., Xie, X., Corey, D. R., & Brugarolas, J. (2011) · The EMBO Journal · doi:10.1038/emboj.2011.257 · Cited by 472
Targeting fibroblast activation protein inhibits tumor stromagenesis and growth in mice
Santos, A., Jung, J. J., Aziz, N., Kissil, J. L., & Puré, E. (2009) · Journal of Clinical Investigation · doi:10.1172/jci38988 · Cited by 436
Role of membrane transport in metabolism and function of glutathione in mammals
Bannai, S., & Tateishi, N. (1986) · The Journal of Membrane Biology · doi:10.1007/bf01870891 · Cited by 386
Understanding metabolic regulation and its influence on cell physiology
Metallo, C. M., & Vander Heiden, M. G. (2013) · Molecular Cell · doi:10.1016/j.molcel.2013.01.018 · Cited by 367
The reactive stroma microenvironment and prostate cancer progression
Barron, D. A., & Rowley, D. R. (2012) · Endocrine Related Cancer · doi:10.1530/erc-12-0085 · Cited by 344
Durán, A., Serrano, M., Leitges, M., Flores, J. M., Picard, S., Brown, J. P., Moscat, J., & Diaz-Meco, M. T. (2004) · Developmental Cell · doi:10.1016/s1534-5807(03)00403-9 · Cited by 316
Self-citationSignal integration and diversification through the p62 scaffold protein
Moscat, J., Díaz-Meco, M. T., & WOOTEN, M. (2006) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2006.12.002 · Cited by 315
Self-citationGalavotti, S., Bartesaghi, S., Faccenda, D., Shaked-Rabi, M., Sanzone, S., McEvoy, A. W., Dinsdale, D. D., Condorelli, F., Brandner, S., Campanella, M., et al. (2012) · Oncogene · doi:10.1038/onc.2012.111 · Cited by 278
IL-6 involvement in epithelial cancers
Schafer, Z. T., & Brugge, J. S. (2007) · Journal of Clinical Investigation · doi:10.1172/jci34237 · Cited by 268
p62: a versatile multitasker takes on cancer
Moscat, J., & Díaz-Meco, M. T. (2012) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2012.02.008 · Cited by 250
Self-citationSánchez‐Gómez, P., de Cárcer, G., Sandoval, I. V., Moscat, J., & Díaz-Meco, M. T. (1998) · Molecular and Cellular Biology · doi:10.1128/mcb.18.5.3069 · Cited by 229
Self-citationInvasive three-dimensional organotypic neoplasia from multiple normal human epithelia
Ridky, T. W., Chow, J. M., Wong, D. J., & Khavari, P. A. (2010) · Nature Medicine · doi:10.1038/nm.2265 · Cited by 217
Accumulation of p62/ SQSTM 1 is associated with poor prognosis in patients with lung adenocarcinoma
Inoue, D., Suzuki, T., Mitsuishi, Y., Miki, Y., Suzuki, S., Sugawara, S., Watanabe, M., Sakurada, A., Endo, C., Uruno, A., et al. (2012) · Cancer Science · doi:10.1111/j.1349-7006.2012.02216.x · Cited by 215
Polarized immune responses differentially regulate cancer development
Johansson, M., DeNardo, D. G., & Coussens, L. M. (2008) · Immunological Reviews · doi:10.1111/j.1600-065x.2008.00600.x · Cited by 214
Control of Nutrient Stress-Induced Metabolic Reprogramming by PKCζ in Tumorigenesis
Ma, L., Tao, Y., Durán, Á., Lladó, V., Galvez, A. S., Barger, J. F., Castilla, E. A., Chen, J., Yajima, T., Porollo, A., et al. (2013) · Cell · doi:10.1016/j.cell.2012.12.028 · Cited by 209
Self-citationThompson, H. G. R., Harris, J. W., Wold, B. J., Lin, F., & Brody, J. P. (2003) · Oncogene · doi:10.1038/sj.onc.1206325 · Cited by 181
SQSTM1 Is a Pathogenic Target of 5q Copy Number Gains in Kidney Cancer
Li, L., Shen, C., Nakamura, E., Ando, K., Signoretti, S., Beroukhim, R., Cowley, G. S., Lizotte, P. H., Liberzon, E., Bair, S. M., et al. (2013) · Cancer Cell · doi:10.1016/j.ccr.2013.10.025 · Cited by 166
Feedback on Fat: p62-mTORC1-Autophagy Connections
Moscat, J., & Díaz-Meco, M. T. (2011) · Cell · doi:10.1016/j.cell.2011.10.021 · Cited by 146
Self-citationDevelopment of a quantitative method to analyse tumour cell invasion in organotypic culture
Nyström, M., Thomas, G. J., Stone, M., Mackenzie, I. C., Hart, I., & Marshall, J. F. (2005) · The Journal of Pathology · doi:10.1002/path.1716 · Cited by 145
The atypical PKCs in inflammation: NF‐κB and beyond
Díaz-Meco, M. T., & Moscat, J. (2012) · Immunological Reviews · doi:10.1111/j.1600-065x.2012.01093.x · Cited by 132
Self-citationLisanti, M. P., Martinez‐Outschoorn, U., & Sotgia, F. (2013) · Cell Cycle · doi:10.4161/cc.25695 · Cited by 123
IL-6/IL-6R as a potential key signaling pathway in prostate cancer development
Azevedo, A. S. (2011) · World Journal of Clinical Oncology · doi:10.5306/wjco.v2.i12.384 · Cited by 122
Rolland, P., Madjd, Z., Durrant, L. G., Ellis, I. O., Layfield, R., & Spendlove, I. (2007) · Endocrine Related Cancer · doi:10.1677/erc.1.01312 · Cited by 115
Schauer, I. G., Ressler, S. J., Tuxhorn, J. A., Dang, T. D., & Rowley, D. R. (2008) · Urology · doi:10.1016/j.urology.2007.11.083 · Cited by 87
Exploiting tumor metabolism: challenges for clinical translation
Heiden, M. G. V. (2013) · Journal of Clinical Investigation · doi:10.1172/jci72391 · Cited by 79
c-Myc phosphorylation by PKCζ represses prostate tumorigenesis
Kim, J. Y., Valencia, T., Abu‐Baker, S., Linares, J., Lee, S. J., Yajima, T., Chen, J., Eroshkin, A. M., Castilla, E. A., Brill, L. M., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1221799110 · Cited by 56
Self-citationTargeting the Tumor Stroma as a Novel Therapeutic Approach for Prostate Cancer
Franco, O. E., & Hayward, S. W. (2012) · Advances in pharmacology · doi:10.1016/b978-0-12-397927-8.00009-9 · Cited by 54
Increased cystine uptake capability associated with malignant progression of Nb2 lymphoma cells
Gout, P., Kang, Y. J., Buckley, D., Bruchovsky, N., & Buckley, A. (1997) · Leukemia · doi:10.1038/sj.leu.2400739 · Cited by 53
Olson, M. V., Lee, J., Zhang, F., Wang, A., & Dong, Z. (2006) · Cancer Gene Therapy · doi:10.1038/sj.cgt.7700941 · Cited by 22
Cited by
Sorted by citations
The biology and function of fibroblasts in cancer
Kalluri, R. (2016) · Nature Reviews Cancer · doi:10.1038/nrc.2016.73 · Cited by 4,366
A framework for advancing our understanding of cancer-associated fibroblasts
Sahai, E., Astsaturov, I., Cukierman, E., DeNardo, D. G., Egeblad, M., Evans, R. M., Fearon, D., Greten, F. R., Hingorani, S. R., Hunter, T., et al. (2020) · Nature Reviews Cancer · doi:10.1038/s41568-019-0238-1 · Cited by 3,863
Autophagy and autophagy-related proteins in cancer
Li, X., He, S., & Ma, B. (2020) · Molecular Cancer · doi:10.1186/s12943-020-1138-4 · Cited by 1,684
Cancer metabolism: a therapeutic perspective
Martinez-Outschoorn, U. E., Peiris-Pagés, M., Pestell, R. G., Sotgia, F., & Lisanti, M. P. (2017) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2016.60 · Cited by 1,505
Autophagy in malignant transformation and cancer progression
Galluzzi, L., Pietrocola, F., Bravo‐San Pedro, J. M., Amaravadi, R. K., Baehrecke, E. H., Cecconi, F., Codogno, P., Debnath, J., Gewirtz, D. A., Karantza, V., et al. (2015) · The EMBO Journal · doi:10.15252/embj.201490784 · Cited by 1,182
Metadata
- Authors
- Valencia, T., Kim, J. Y., Abu-Baker, S., Moscat-Pardos, J., Ahn, C. S., Reina-Campos, M., Duran, A., Castilla, E. A., Metallo, C. M., Diaz-Meco, M. T., & Moscat, J.
- Affiliations
- Sanford Burnham Prebys Medical Discovery Institute (US)
- University of California San Diego (US)
- University of Cincinnati (US)
- Corresponding author
- Moscat, Jorge
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2014-07
- Volume
- 26
- Issue
- 1
- Pages
- 121-135
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC4101061
- OpenAlex
- W2113240092
- Cited by
- 304
- References
- 62
- Citations by year
- 2026: 6 · 2025: 17 · 2024: 13 · 2023: 12 · 2022: 29 · 2021: 41 · 2020: 37 · 2019: 34 · 2018: 28 · 2017: 27 · 2016: 31 · 2015: 23 · 2014: 6
- FWCI
- 9.29
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Cancer Institute (R01CA132847, R01CA172025, R01CA134530, P30CA030199)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- 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
- Keywords
- p62, mTORC1, stromal fibroblasts, tumor microenvironment, metabolic reprogramming, prostate cancer, c-Myc, interleukin-6, inflammation, carcinogenesis, redox regulation, glucose metabolism, amino acid metabolism, tumor stroma
- MeSH terms
- Sequestosome-1 Protein, Mechanistic Target of Rapamycin Complex 1, Amino Acids, Animals, Cell Communication, Cell Transformation, Neoplastic, Energy Metabolism, Fibroblasts, Glucose, Heat-Shock Proteins, Humans, Inflammation, Male, Mice, Inbred C57BL, Neoplasm Invasiveness, Prostatic Hyperplasia, Prostatic Neoplasms, Time Factors, Transfection, Signal Transduction, Interleukin-6, Proto-Oncogene Proteins c-myc, Stromal Cells, Mice, Knockout, Oxidative Stress, Inflammation Mediators, Coculture Techniques, Prostatic Intraepithelial Neoplasia, RNA Interference, Cell Line, Tumor, Multiprotein Complexes, Adaptor Proteins, Signal Transducing, PTEN Phosphohydrolase, Mice, HEK293 Cells, TOR Serine-Threonine Kinases, Tumor Microenvironment
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
