Autocrine signaling is a form of cell 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 with paracrine signaling, intracrine signaling, or classical endocrine signaling.
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.[ citation needed ]
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.[ citation needed ]
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 signaling plays critical roles in cancer activation and also in providing self-sustaining growth signals to tumors.[ citation needed ]
Normally, the Wnt signaling 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 signaling pathway via mutations in APC and Axin have been linked to activation of various types of human cancer. [2] [3] 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 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 a cytokine that is important for many aspects of cellular biology including immune responses, cell survival, apoptosis, as well as proliferation. [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-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 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 induced malignant 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 is vascular endothelial growth factor (VEGF). VEGF, produced by carcinoma cells, acts through paracrine signaling on endothelial 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 to angiogenesis. 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 autocrine PDGFR signaling 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 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 Wnt antagonists or other molecules that interfere with ligand-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 by phosphorylation and activation of VEGFR-2. This autocrine loop is another example of an attractive therapeutic 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 a dominant-negative PDGFR or application of the cancer drug STI571 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-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 signaling, the Smac mimetic promotes formation of a RIPK1-dependent caspase-8-activating complex, leading to apoptosis. [13]
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 signaling 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. [14]
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 signaling suggest a novel strategy for management of patients with tamoxifen-resistant tumors. [15]
Gefitinib, sold under the brand name Iressa, is a medication used for certain breast, lung and other cancers. Gefitinib is an EGFR inhibitor, like erlotinib, which interrupts signaling through the epidermal growth factor receptor (EGFR) in target cells. Therefore, it is only effective in cancers with mutated and overactive EGFR, but resistances to gefitinib can arise through other mutations. It is marketed by AstraZeneca and Teva.
The Wnt signaling pathways are a group of signal transduction pathways which begin with proteins that pass signals into a cell through cell surface receptors. The name Wnt is a portmanteau created from the names Wingless and Int-1. Wnt signaling pathways use either nearby cell-cell communication (paracrine) or same-cell communication (autocrine). They are highly evolutionarily conserved in animals, which means they are similar across animal species from fruit flies to humans.
A mitogen is a small bioactive protein or peptide that induces a cell to begin cell division, or enhances the rate of division (mitosis). Mitogenesis is the induction (triggering) of mitosis, typically via a mitogen. The mechanism of action of a mitogen is that it triggers signal transduction pathways involving mitogen-activated protein kinase (MAPK), leading to mitosis.
Hepatocyte growth factor receptor is a protein that in humans is encoded by the MET gene. The protein possesses tyrosine kinase activity. The primary single chain precursor protein is post-translationally cleaved to produce the alpha and beta subunits, which are disulfide linked to form the mature receptor.
Receptor tyrosine-protein kinase erbB-2 is a protein that normally resides in the membranes of cells and is encoded by the ERBB2 gene. ERBB is abbreviated from erythroblastic oncogene B, a gene originally isolated from the avian genome. The human protein is also frequently referred to as HER2 or CD340.
Targeted therapy or molecularly targeted therapy is one of the major modalities of medical treatment (pharmacotherapy) for cancer, others being hormonal therapy and cytotoxic chemotherapy. As a form of molecular medicine, targeted therapy blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth, rather than by simply interfering with all rapidly dividing cells. Because most agents for targeted therapy are biopharmaceuticals, the term biologic therapy is sometimes synonymous with targeted therapy when used in the context of cancer therapy. However, the modalities can be combined; antibody-drug conjugates combine biologic and cytotoxic mechanisms into one targeted therapy.
Lapatinib (INN), used in the form of lapatinib ditosylate (USAN) is an orally active drug for breast cancer and other solid tumours. It is a dual tyrosine kinase inhibitor which interrupts the HER2/neu and epidermal growth factor receptor (EGFR) pathways. It is used in combination therapy for HER2-positive breast cancer. It is used for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 (ErbB2).
Platelet-derived growth factor receptors (PDGF-R) are cell surface tyrosine kinase receptors for members of the platelet-derived growth factor (PDGF) family. PDGF subunits -A and -B are important factors regulating cell proliferation, cellular differentiation, cell growth, development and many diseases including cancer. There are two forms of the PDGF-R, alpha and beta each encoded by a different gene. Depending on which growth factor is bound, PDGF-R homo- or heterodimerizes.
Interleukin 30 (IL-30) forms one chain of the heterodimeric cytokine called interleukin 27 (IL-27), thus it is also called IL27-p28. IL-27 is composed of α chain p28 and β chain Epstain-Barr induce gene-3 (EBI3). The p28 subunit, or IL-30, has an important role as a part of IL-27, but it can be secreted as a separate monomer and has its own functions in the absence of EBI3. The discovery of IL-30 as individual cytokine is relatively new and thus its role in the modulation of the immune response is not fully understood.
Cripto is an EGF-CFC or epidermal growth factor-CFC, which is encoded by the Cryptic family 1 gene. Cryptic family protein 1B is a protein that in humans is encoded by the CFC1B gene. Cryptic family protein 1B acts as a receptor for the TGF beta signaling pathway. It has been associated with the translation of an extracellular protein for this pathway. The extracellular protein which Cripto encodes plays a crucial role in the development of left and right division of symmetry.
The ErbB family of proteins contains four receptor tyrosine kinases, structurally related to the epidermal growth factor receptor (EGFR), its first discovered member. In humans, the family includes Her1, Her2 (ErbB2), Her3 (ErbB3), and Her4 (ErbB4). The gene symbol, ErbB, is derived from the name of a viral oncogene to which these receptors are homologous: erythroblastic leukemia viral oncogene. Insufficient ErbB signaling in humans is associated with the development of neurodegenerative diseases, such as multiple sclerosis and Alzheimer's disease, while excessive ErbB signaling is associated with the development of a wide variety of types of solid tumor.
Receptor tyrosine-protein kinase erbB-3, also known as HER3, is a membrane bound protein that in humans is encoded by the ERBB3 gene.
Proto-oncogene tyrosine-protein kinase Src, also known as proto-oncogene c-Src, or simply c-Src, is a non-receptor tyrosine kinase protein that in humans is encoded by the SRC gene. It belongs to a family of Src family kinases and is similar to the v-Src gene of Rous sarcoma virus. It includes an SH2 domain, an SH3 domain and a tyrosine kinase domain. Two transcript variants encoding the same protein have been found for this gene.
Sulfatase 1, also known as SULF1, is an enzyme which in humans is encoded by the SULF1 gene.
Afatinib, sold under the brand name Gilotrif among others, is a medication which is used to treat non-small cell lung carcinoma (NSCLC). It belongs to the tyrosine kinase inhibitor family of medications. It is taken by mouth.
Angiokinase inhibitors are a new therapeutic target for the management of cancer. They inhibit tumour angiogenesis, one of the key processes leading to invasion and metastasis of solid tumours, by targeting receptor tyrosine kinases. Examples include nintedanib, afatinib and motesanib.
VEGFR-2 inhibitor, also known as kinase insert domain receptor(KDR) inhibitor, are tyrosine kinase receptor inhibitors that reduce angiogenesis or lymphangiogenesis, leading to anticancer activity. Generally they are small, synthesised molecules that bind competitively to the ATP-site of the tyrosine kinase domain. VEGFR-2 selective inhibitor can interrupt multiple signaling pathways involved in tumor, including proliferation, metastasis and angiogenesis.
hPG80 refers to the extracellular and oncogenic version of progastrin. This name first appeared in a scientific publication in January 2020. Until that date, scientific publications only mention 'progastrin', without necessarily explicitly specifying whether it is intracellular or extracellular in the tumor pathological setting.
MIR22HG, also known as C17orf91, MGC14376, MIRN22, hsa-mir-22, and miR-22 is a human gene that encodes a noncoding RNA (ncRNA).This RNA molecule is not translated into a protein but nonetheless may have important functions.
Endocrine therapy is a common treatment for estrogen receptor positive breast cancer. However, resistance to this therapy can develop, leading to relapse and progression of disease. This highlights the need for new strategies to combat this resistance.