Autocrine signaling is a form ofcell signaling in 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,intracrine signaling, or classicalendocrine signaling.
An example of an autocrine agent is thecytokineinterleukin-1 inmonocytes. When interleukin-1 is produced in response to external stimuli, it can bind to cell-surfacereceptors on 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:MHC complex on aprofessional antigen-presenting cell and by theB7:CD28 costimulatory signal. Upon activation, "low-affinity"IL-2 receptors 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 amonoclonal population of T cells. These T cells can then go on to perform effector functions such asmacrophage activation,B cell activation, and cell-mediatedcytotoxicity.[citation needed]
Tumor development 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]
Normally, theWnt signaling pathway leads to stabilization ofβ-catenin through inactivation of a protein complex containing the tumor suppressorsAPC andAxin. This destruction complex normally triggers β-cateninphosphorylation, inducing its degradation. De-regulation of the autocrine Wnt signaling pathway viamutations in 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 andtranscription ofgenes encoding 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]
Interleukin 6 (acronym: IL-6) is acytokine that is important for many aspects ofcellular biology includingimmune 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 theoncogenic STAT3 pathway via upregulated IL-6 autocrine signaling.[5]
Similarly,HER2 overexpression 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 inducedmalignant features in Notch-3 expressing mammospheres.[7]
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]
Another agent involved in autocrine cancer signaling isvascular endothelial growth factor (VEGF). VEGF, produced by carcinoma cells, acts throughparacrine signaling onendothelial cells and 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]
Metastasis is a major cause of cancer deaths, and strategies to prevent or halt invasion are lacking. One study showed that autocrinePDGFR signaling 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.
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 Wntantagonists or other molecules that interfere withligand-receptor interactions 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 byphosphorylation and 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-negative PDGFR or application of the cancer drugSTI571 are 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-moleculemimetic ofSmac/Diablo that counteracts the inhibition of apoptosis has been shown to enhance apoptosis caused bychemotherapeutic drugs through 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]
Recent studies have reported the ability ofdrug-resistant cancer cells to acquiremitogenic signals from previously neglected autocrine loops, causing tumor recurrence.
For example, despite widespread expression ofepidermal growth factor receptors (EGFRs) and EGF familyligands innon-small-cell lung cancer (NSCLC), EGFR-specifictyrosine kinase inhibitors such asgefitinib have 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 profiling revealed 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 oftamoxifen resistance is another major therapeutic problem. It has been shown that phosphorylation of STAT3 andRANTES expression 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 inhibitingcaspase cleavage. These mechanisms of STAT3-RANTES autocrine signaling suggest a novel strategy for management of patients with tamoxifen-resistant tumors.[15]