GDF-15 in Cancer Progression, Systemic and Immune Response
GDF-15 is generally considered to be part of the cell's antitumorigenic actions, largely because its expression is crucial for the chemopreventive effects of various compounds.[57,58] However, elevated GDF-15 expression has often been reported during cancer progression, including gastric, ovarian, prostate or breast cancers (see Table 1) with various impact on tumors.[4,65,66] Despite that the GDF-15 expression profile has been well described in various cancers, its specific role in tumor development remains unclear (Figure 1). For example, in breast or gastric cancer, GDF-15 has been shown to be upregulated upon the activation of the MAPK-ERK1/2 or PKB/Akt pathways recruiting the SP-1 family of transcription factors. GDF-15 also induces the phosphorylation and activation of ErbB receptors, mTOR/Akt and ERK1/2 pathways. A potential result of these signal integrations is HIF-1 and VEGF activation. Moreover, inhibition or specific downregulation of ErbB2 also inhibited GDF-15-mediated downstream signaling. These findings indicate the importance of GDF-15 clinically, especially in ErbB2 (HER2)-positive cancers that are sensitive to small molecular inhibitors, such as lapatinib. GDF-15 is strongly upregulated in hepatocellular carcinoma and other liver diseases, such as fibrosis or cirrhosis induced by hepatitis C virus. GDF-15 autocrine signaling of transformed or infected hepatocytes then induces Akt, GSK-3/β catenin, Raf phosphorylation and other downstream targets, such as cell-cycle regulators (cyclins A2, E1 and D2) or adhesion molecules (E-cadherin). Interestingly, impairing GDF-15 can inhibit viral replication. In malignant melanomas, GDF-15 is highly overexpressed, and it is able to mimic VEGF in the neovascularization in the tumor site. Similarly, in malignant glioblastomas, GDF-15 is upregulated as a reaction to anoxia, suggesting more general involvement in vascularization development. Moreover, experimental decrease in GDF-15 expression clearly enhanced natural killer T-cell-mediated cytotoxicity, which increased the immunogenicity of glioma cells similar to the effects of TGF-β downregulation. Furthermore, GDF-15 depletion delays the growth of gliomas in mice in vivo. It is likely that GDF-15 acts as a potent suppressor of immune cells while simultaneously enhancing cancer cell growth through autocrine signaling. These observations emphasize the importance of assessing the role of the interactions within the tumor microenvironment for a context-dependent role of GDF-15. Interestingly, two antagonistic in vivo studies were published recently. Senapati et al. demonstrated that ectopic overexpression of GDF-15 led to increased dissemination capacity of PCa cells. However, Zimmers et al. showed that loss of GDF-15 expression abolished the chemopreventive effects of NSAIDs in animal models of hereditary colon cancer.
Schematic illustration of growth/differentiation factor-15 (GDF-15) action in tissue microenvironment and cancer progression. (a) GDF-15 is secreted by a primary tumor or released from extracellular matrix, affecting both the tumor and adjacent stromal or immune cells responsive to GDF-15. (b) GDF-15 is released to blood stream and contributing to tumor spreading, vascularization and immunosuppression. (c) GDF-15 is involved in remodeling of bone architecture by action on both osteoblasts and osteoclasts, affecting the bone-marrow microenvironment and stem-cell niche formation. (d) GDF-15 expression is induced upon various stimuli, for example, by p53 and/or Sp1-Egr-1 dependent transcription. GDF-15 induces signaling pathway comprising of so far identified SMAD, MAPK and Akt and activating transcription from SMAD, AP-1 and Sp-1 driven promoters.
Thus, the primary effect of GDF-15 on cancer progression can be linked to the regulation of immune responses in the process of tissue regeneration. GDF-15 has been described as a negative regulator of macrophage activation by suppressing the release of TNF-α, IL-1, IL-2 and MCS-F, thus inhibiting the positive feedback of local inflammatory signaling similar to the effects of TGF-β. However, the molecular mechanisms behind these immunosuppressive effects remain unclear despite several hypotheses that focus on interactions with regulatory T lymphocytes in a context already defined for TGF-β in various cancers.[42,77] Taken together, the cancer-associated elevated expression of GDF-15 may have strong predictive potential that could justify the introduction of GDF-15 clinically as a biomarker for particular cancers. Moreover, focusing on its immunosuppressive characteristics, GDF-15 may be specifically targeted to restore the immune-mediated anti-tumor response.
Prostate Cancer Prostatic Dis. 2012;15(4):320-328. © 2012 Nature Publishing Group