Autocrine signaling

Source: Wikipedia, the free encyclopedia.

Autocrine signaling is a form of

endocrine
signaling.

Examples

An example of an autocrine agent is the

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

]

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 signaling plays critical roles in cancer activation and also in providing self-sustaining growth signals to tumors.[citation needed
]

In the Wnt pathway

Normally, the

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]

IL-6

oncogenic STAT3 pathway via upregulated IL-6 autocrine signaling.[5]

Similarly,

malignant features in Notch-3 expressing mammospheres.[7]

IL-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]

VEGF

Another agent involved in autocrine cancer signaling is

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]

Promotion of metastasis

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.

Development of therapeutic targets

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

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

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]

Role in drug resistance

Recent studies have reported the ability of

mitogenic
signals from previously neglected autocrine loops, causing tumor recurrence.

For example, despite widespread expression of

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

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]

See also

References

External links