Wikipedia

Autocrine signaling

Autocrine signalingis a form ofcell signalingin which a cell secretes a hormone or chemical messenger (called the autocrine agent) that binds to autocrine receptors on that same cell, leading to changes in the cell.[1]This can be contrasted withparacrine signaling,intracrinesignaling, or classicalendocrinesignaling.

Examples

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An example of an autocrine agent is thecytokineinterleukin-1inmonocytes.When interleukin-1 is produced in response to external stimuli, it can bind to cell-surfacereceptorson the same cell that produced it.[citation needed]

Another example occurs in activatedT celllymphocytes,i.e., when a T cell is induced to mature by binding to apeptide:MHCcomplex on aprofessional antigen-presenting celland by theB7:CD28costimulatory signal. Upon activation, "low-affinity"IL-2receptors are replaced by "high-affinity" IL-2 receptors consisting of α, β, and γ chains. The cell then releases IL-2, which binds to its own new IL-2 receptors, causing self-stimulation and ultimately amonoclonalpopulation of T cells. These T cells can then go on to perform effector functions such asmacrophageactivation,B cellactivation, and cell-mediatedcytotoxicity.[citation needed]

Cancer

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Tumordevelopment is a complex process that requirescell division,growth, and survival. One approach used by tumors to upregulate growth and survival is through autocrine production of growth and survival factors. Autocrine signaling plays critical roles in cancer activation and also in providing self-sustaining growth signals to tumors.[citation needed]

In the Wnt pathway

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Normally, theWnt signaling pathwayleads to stabilization ofβ-cateninthrough inactivation of a protein complex containing the tumor suppressorsAPCandAxin.This destruction complex normally triggers β-cateninphosphorylation,inducing its degradation. De-regulation of the autocrine Wnt signaling pathway viamutationsin APC and Axin have been linked to activation of various types of humancancer.[2][3]Genetic alterations that lead to de-regulation of the autocrine Wnt pathway result in transactivation ofepidermal growth factor receptor(EGFR) and other pathways, in turn contributing to proliferation of tumor cells. Incolorectal cancer,for example, mutations in APC, axin, or β-catenin promote β-catenin stabilization andtranscriptionofgenesencoding cancer-associatedproteins.Furthermore, in humanbreast cancer,interference with the de-regulated Wnt signaling pathway reduces proliferation and survival of cancer. These findings suggest that interference with Wnt signaling at the ligand-receptor level may improve the effectiveness of cancer therapies.[3]

IL-6

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Interleukin 6(acronym: IL-6) is acytokinethat is important for many aspects ofcellular biologyincludingimmune responses,cell survival,apoptosis,as well asproliferation.[4]Several studies have outlined the importance of autocrine IL-6 signaling in lung and breast cancers. For example, one group found a positive correlation between persistently activated tyrosine-phosphorylatedSTAT3(pSTAT3), found in 50% of lung adenocarcinomas, and IL-6. Further investigation revealed that mutant EGFR could activate theoncogenicSTAT3 pathway via upregulated IL-6 autocrine signaling.[5]

Similarly,HER2overexpression occurs in approximately a quarter of breast cancers and correlates with poor prognosis. Recent research revealed that IL-6 secretion induced by HER2 overexpression activated STAT3 and altered gene expression, resulting in an autocrine loop of IL-6/STAT3 expression. Both mouse and human in vivo models of HER2-overexpressing breast cancers relied critically on this HER2–IL-6–STAT3 signaling pathway.[6]Another group found that high serum levels of IL-6 correlated with poor outcome in breast cancer tumors. Their research showed that autocrine IL-6 signaling inducedmalignantfeatures in Notch-3 expressing mammospheres.[7]

IL-7

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A study demonstrates how the autocrine production of the IL-7 cytokine mediated by T-cell acute lymphoblastic leukemia (T-ALL) can be involved in the oncogenic development of T-ALL and offer novel insights into T-ALL spreading.[8]

VEGF

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Another agent involved in autocrine cancer signaling isvascular endothelial growth factor(VEGF). VEGF, produced by carcinoma cells, acts throughparacrine signalingonendothelial cellsand through autocrine signaling on carcinoma cells.[9]Evidence shows that autocrine VEGF is involved in two major aspects of invasive carcinoma: survival and migration. Moreover, it was shown that tumor progression selects for cells that are VEGF-dependent, challenging the belief that VEGF's role in cancer is limited toangiogenesis.Instead, this research suggests that VEGF receptor-targeted therapeutics may impair cancer survival and invasion as well as angiogenesis.[9][10]

Promotion of metastasis

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Metastasisis a major cause of cancer deaths, and strategies to prevent or halt invasion are lacking. One study showed that autocrinePDGFRsignaling plays an essential role inepithelial-mesenchymal transition(EMT) maintenance in vitro, which is known to correlate well with metastasis in vivo. The authors showed that the metastatic potential of oncogenic mammary epithelial cells required an autocrine PDGF/PDGFR signaling loop, and that cooperation of autocrine PDGFR signaling with oncogenic was required for survival during EMT. Autocrine PDGFR signaling also contributes to maintenance of EMT, possibly through activation of STAT1 and other distinct pathways. In addition, expression of PDGFRα and -β correlated with invasive behavior in human mammary carcinomas.[11]This indicates the numerous pathways through which autocrine signaling can regulate metastatic processes in a tumor.

Development of therapeutic targets

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The growing knowledge behind the mechanism of autocrine signaling in cancer progression has revealed new approaches for therapeutic treatment. For example, autocrine Wnt signaling could provide a novel target for therapeutic intervention by means of Wntantagonistsor other molecules that interfere withligand-receptorinteractions of the Wnt pathway.[2][3]In addition, VEGF-A production and VEGFR-2 activation on the surface of breast cancer cells indicates the presence of a distinct autocrine signaling loop that enables breast cancer cells to promote their own growth and survival byphosphorylationand activation of VEGFR-2. This autocrine loop is another example of an attractivetherapeutic target.[9]

In HER2 overexpressing breast cancers, the HER2–IL-6–STAT3 signaling relationship could be targeted to develop new therapeutic strategies.[6]HER2 kinase inhibitors, such as lapatinib, have also demonstrated clinical efficacy in HER2 overexpressing breast cancers by disrupting a neuregulin-1 (NRG1)-mediated autocrine loop.[12]

In the case of PDGFR signalling, overexpression of adominant-negativePDGFR or application of the cancer drugSTI571are both approaches being explored to therapeutically interference with metastasis in mice.[11]

In addition, drugs may be developed that activate autocrine signaling in cancer cells that would not otherwise occur. For example, a small-moleculemimeticofSmac/Diablo that counteracts the inhibition of apoptosis has been shown to enhance apoptosis caused bychemotherapeutic drugsthrough autocrine-secretedtumor necrosis factor Alpha(TNFα). In response to autocrine TNFα signaling, the Smac mimetic promotes formation of a RIPK1-dependent caspase-8-activating complex, leading to apoptosis.[13]

Role in drug resistance

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Recent studies have reported the ability ofdrug-resistantcancer cells to acquiremitogenicsignals from previously neglected autocrine loops, causing tumor recurrence.

For example, despite widespread expression ofepidermal growth factorreceptors (EGFRs) and EGF familyligandsinnon-small-cell lung cancer(NSCLC), EGFR-specifictyrosine kinase inhibitorssuch asgefitinibhave shown limited therapeutic success. This resistance is proposed to be because autocrine growth signaling pathways distinct from EGFR are active in NSCLC cells.Gene expression profilingrevealed the prevalence of specificfibroblast growth factors(FGFs) and FGF receptors in NSCLC cell lines, and found that FGF2, FGF9 and their receptors encompass a growth factor autocrine loop that is active in a subset of gefitinib-resistant NSCLC cell lines.[14]

In breast cancer, the acquisition oftamoxifenresistance is another major therapeutic problem. It has been shown that phosphorylation of STAT3 andRANTESexpression are increased in response to tamoxifen in human breast cancer cells. In a recent study, one group showed that STAT3 and RANTES contribute to the maintenance of drug resistance by upregulating anti-apoptotic signals and inhibitingcaspasecleavage. These mechanisms of STAT3-RANTES autocrine signaling suggest a novel strategy for management of patients with tamoxifen-resistant tumors.[15]

See also

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References

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  1. ^Pandit, Nikita K. (2007).Introduction To The Pharmaceutical Sciences.Lippincott Williams & Wilkins. p.238.ISBN978-0-7817-4478-2.
  2. ^abBafico, Anna; Liu, Guizhong; Goldin, Luba; Harris, Violaine; Aaronson, Stuart A. (2004)."An autocrine mechanism for constitutive Wnt pathway activation in human cancer cells".Cancer Cell.6(5): 497–506.doi:10.1016/j.ccr.2004.09.032.PMID15542433.
  3. ^abcSchlange, Thomas; Matsuda, Yutaka; Lienhard, Susanne; Huber, Alexandre; Hynes, Nancy E (2007)."Autocrine WNT signaling contributes to breast cancer cell proliferation via the canonical WNT pathway and EGFR transactivation".Breast Cancer Research.9(5): R63.doi:10.1186/bcr1769.PMC2242658.PMID17897439.
  4. ^Grivennikov, Sergei; Karin, Michael (2008)."Autocrine IL-6 Signaling: A Key Event in Tumorigenesis?".Cancer Cell.13(1): 7–9.doi:10.1016/j.ccr.2007.12.020.PMID18167335.
  5. ^Gao, Sizhi Paul; Mark, Kevin G.; Leslie, Kenneth; Pao, William; Motoi, Noriko; Gerald, William L.; Travis, William D.; Bornmann, William; Veach, Darren; Clarkson, Bayard; Bromberg, Jacqueline F. (2007)."Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 production in human lung adenocarcinomas".Journal of Clinical Investigation.117(12): 3846–56.doi:10.1172/JCI31871.PMC2096430.PMID18060032.
  6. ^abHartman, Zachary C.; Yang, Xiao-Yi; Glass, Oliver; Lei, Gangjun; Osada, Takuya; Dave, Sandeep S.; Morse, Michael A.; Clay, Timothy M.; Lyerly, Herbert Kim (2011)."HER2 Overexpression Elicits a Proinflammatory IL-6 Autocrine Signaling Loop That is Critical for Tumorigenesis".Cancer Research.71(13): 4380–91.doi:10.1158/0008-5472.CAN-11-0308.PMC3129398.PMID21518778.
  7. ^Sansone, Pasquale; Storci, Gianluca; Tavolari, Simona; Guarnieri, Tiziana; Giovannini, Catia; Taffurelli, Mario; Ceccarelli, Claudio; Santini, Donatella; Paterini, Paola; Marcu, Kenneth B.; Chieco, Pasquale; Bonafè, Massimiliano (2007)."IL-6 triggers malignant features in mammospheres from human ductal breast carcinoma and normal mammary gland".Journal of Clinical Investigation.117(12): 3988–4002.doi:10.1172/JCI32533.PMC2096439.PMID18060036.
  8. ^Buffière A, Uzan B, Aucagne R, Hermetet F, Mas M, Nassurdine S, Aznague A, Carmignac V, Tournier B, Bouchot O, Ballerini P, Barata JT, Bastie JN, Delva L, Pflumio F, Quéré R (November 2019). "T-cell acute lymphoblastic leukemia displays autocrine production of Interleukin-7".Oncogene.38(1): 7357–7365.doi:10.1038/s41388-019-0921-4.PMID31417180.S2CID199668368.
  9. ^abcWeigand, Melanie; Hantel, Pia; Kreienberg, Rolf; Waltenberger, Johannes (2005). "Autocrine vascular endothelial growth factor signaling in breast cancer. Evidence from cell lines and primary breast cancer cultures in vitro".Angiogenesis.8(3): 197–204.doi:10.1007/s10456-005-9010-0.PMID16328160.S2CID25711624.
  10. ^Mercurio, Arthur M; Bachelder, Robin E; Bates, Richard C; Chung, Jun (2004). "Autocrine signaling in carcinoma: VEGF and the α6β4 integrin".Seminars in Cancer Biology.14(2): 115–22.doi:10.1016/j.semcancer.2003.09.016.PMID15018895.
  11. ^abJechlinger, M.; Sommer, A; Moriggl, R; Seither, P; Kraut, N; Capodiecci, P; Donovan, M;Cordon-Cardo, C;Beug, H; Grünert, S (2006)."Autocrine PDGFR signaling promotes mammary cancer metastasis".Journal of Clinical Investigation.116(6): 1561–70.doi:10.1172/JCI24652.PMC1469776.PMID16741576.
  12. ^Wilson, Timothy R.; Lee, Diana Y.; Berry, Leanne; Shames, David S.; Settleman, Jeff (2011)."Neuregulin-1-Mediated Autocrine Signaling Underlies Sensitivity to HER2 Kinase Inhibitors in a Subset of Human Cancers".Cancer Cell.20(2): 158–72.doi:10.1016/j.ccr.2011.07.011.PMID21840482.
  13. ^Petersen, Sean L.; Wang, Lai; Yalcin-Chin, Asligul; Li, Lin; Peyton, Michael; Minna, John; Harran, Patrick; Wang, Xiaodong (2007)."Autocrine TNFα Signaling Renders Human Cancer Cells Susceptible to Smac-Mimetic-Induced Apoptosis".Cancer Cell.12(5): 445–56.doi:10.1016/j.ccr.2007.08.029.PMC3431210.PMID17996648.
  14. ^Marek, Lindsay; Ware, Kathryn E.; Fritzsche, Alexa; Hercule, Paula; Helton, Wallace R.; Smith, Jennifer E.; McDermott, Lee A.; Coldren, Christopher D.; Nemenoff, Raphael A.; Merrick, D. T.; Helfrich, B. A.; Bunn Jr, P. A.; Heasley, L. E. (2008)."Fibroblast Growth Factor (FGF) and FGF Receptor-Mediated Autocrine Signaling in Non-Small-Cell Lung Cancer Cells".Molecular Pharmacology.75(1): 196–207.doi:10.1124/mol.108.049544.PMC2669785.PMID18849352.
  15. ^Yi, Eun Hee; Lee, Chang Seok; Lee, Jin-Ku; Lee, Young Ju; Shin, Min Kyung; Cho, Chung-Hyun; Kang, Keon Wook; Lee, Jung Weon; Han, Wonshik; Noh, D.-Y.; Kim, Y.-N.; Cho, I.-H.; Ye, S.-k. (2012)."STAT3-RANTES Autocrine Signaling is Essential for Tamoxifen Resistance in Human Breast Cancer Cells".Molecular Cancer Research.11(1): 31–42.doi:10.1158/1541-7786.MCR-12-0217.PMID23074171.
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