Autocrine signalling is a form of cell signalling 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. This can be contrasted with paracrine signalling, intracrine signalling, or classical endocrine signalling.
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Examples
An example of an autocrine agent is the cytokine interleukin-1 in monocytes. When interleukin-1 is produced in response to external stimuli, it can bind to cell-surface receptors on the same cell that produced it.
Another example occurs in activated T cell lymphocytes, i.e., when a T cell is induced to mature by binding to a peptide:MHC complex on a professional antigen-presenting cell and by the B7: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 a monoclonal population of T cells. These T cells can then go on to perform effector functions such as macrophage activation, B cell activation, and cell-mediated cytoxicity.
Cancer
Tumor development is a complex process that requires cell division, growth, and survival. One approach used by tumors to upregulate growth and survival is through autocrine production of growth and survival factors. Autocrine signalling plays critical roles in cancer activation and also in providing self-sustaining growth signals to tumors.
In the Wnt pathway
Normally, the Wnt signalling pathway leads to stabilization of β-catenin through inactivation of a protein complex containing the tumor suppressors APC and Axin. This destruction complex normally triggers β-catenin phosphorylation, inducing its degradation. De-regulation of the autocrine Wnt signalling pathway via mutations in APC and Axin have been linked to activation of various types of human cancer. Genetic alterations that lead to de-regulation of the autocrine Wnt pathway result in transactivation of epidermal growth factor receptor (EGFR) and other pathways, in turn contributing to proliferation of tumor cells. In colorectal cancer, for example, mutations in APC, axin, or β-catenin promote β-catenin stabilization and transcription of genes encoding cancer-associated proteins. Furthermore, in human breast cancer, interference with the de-regulated Wnt signalling pathway reduces proliferation and survival of cancer. These findings suggest that interference with Wnt signalling at the ligand-receptor level may improve the effectiveness of cancer therapies.
IL-6
Interleukin 6 (IL-6) is a cytokine that is important for many aspects of cellular biology including immune responses, cell survival, apoptosis, and proliferation. Several studies have outlined the importance of autocrine IL-6 signalling in lung and breast cancers. For example, one group found a positive correlation between persistently activated tyrosine-phosphorylated STAT3 (pSTAT3), found in 50% of lung adenocarcinomas, and IL-6. Further investigation revealed that mutant EGFR could activate the oncogenic STAT3 pathway via upregulated IL-6 autocrine signalling.
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 signalling pathway. 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 induced malignant features in Notch-3 expressing mammospheres.
VEGF
Another agent involved in autocrine cancer signalling is vascular endothelial growth factor (VEGF). VEGF, produced by carcinoma cells, acts through paracrine signalling on endothelial cells and through autocrine signalling on carcinoma cells. 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 to angiogenesis. Instead, this research suggests that VEGF receptor-targeted therapeutics may impair cancer survival and invasion as well as angiogenesis.
Promotion of metastasis
Metastasis is a major cause of cancer deaths, and strategies to prevent or halt invasion are lacking. One study showed that autocrine PDGFR signalling plays an essential role in epithelial-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 signalling loop, and that cooperation of autocrine PDGFR signalling with oncogenic was required for survival during EMT. Autocrine PDGFR signalling 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. This indicates the numerous pathways through which autocrine signalling can regulate metastatic processes in a tumor.
Development of therapeutic targets
The growing knowledge behind the mechanism of autocrine signalling in cancer progression has revealed new approaches for therapeutic treatment. For example, autocrine Wnt signalling could provide a novel target for therapeutic intervention by means of Wnt antagonists or other molecules that interfere with ligand-receptor interactions of the Wnt pathway. In addition, VEGF-A production and VEGFR-2 activation on the surface of breast cancer cells indicates the presence of a distinct autocrine signalling loop that enables breast cancer cells to promote their own growth and survival by phosphorylation and activation of VEGFR-2. This autocrine loop is another example of an attractive therapeutic target.
In HER2 overexpressing breast cancers, the HER2–IL-6–STAT3 signalling relationship could be targeted to develop new therapeutic strategies. 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.
In the case of PDGFR signalling, overexpression of a dominant-negative PDGFR or application of the cancer drug STI571 are both approaches being explored to therapeutically interference with metastasis in mice.
In addition, drugs may be developed that activate autocrine signalling in cancer cells that would not otherwise occur. For example, a small-molecule mimetic of Smac/Diablo that counteracts the inhibition of apoptosis has been shown to enhance apoptosis caused by chemotherapeutic drugs through autocrine-secreted tumor necrosis factor alpha (TNFα). In response to autocrine TNFα signalling, the Smac mimetic promotes formation of a RIPK1-dependent caspase-8-activating complex, leading to apoptosis.
Role in drug resistance
Recent studies have reported the ability of drug-resistant cancer cells to acquire mitogenic signals from previously neglected autocrine loops, causing tumor recurrence.
For example, despite widespread expression of epidermal growth factor receptors (EGFRs) and EGF family ligands in non-small-cell lung cancer (NSCLC), EGFR-specific tyrosine kinase inhibitors such as gefitinib have shown limited therapeutic success. This resistance is proposed to be because autocrine growth signalling pathways distinct from EGFR are active in NSCLC cells. Gene expression profiling revealed the prevalence of specific fibroblast 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.
In breast cancer, the acquisition of tamoxifen resistance is another major therapeutic problem. It has been shown that phosphorylation of STAT3 and RANTES 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 inhibiting caspase cleavage. These mechanisms of STAT3-RANTES autocrine signalling suggest a novel strategy for management of patients with tamoxifen-resistant tumors.