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.
In the Wnt pathway 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. 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. 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. 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. 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.
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.
VEGF 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. 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 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. 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. 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.
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 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. 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. ==See also==