CTGF-mediated autophagy-senescence transition in tumor stroma promotes anabolic tumor growth and metastasis

Comment on: Capparelli C, et al. Cell Cycle 2012; 11:2272-84 and Capparelli C, et al. Cell Cycle 2012; 11:2285-302.Otto Warburg first observed that cancer cells preferentially undergo glycolysis instead of the mitochondrial TCA cycle even under oxygen-rich conditions. This form of energy metabolism in cancer cells is called “aerobic glycolysis” or the “Warburg effect.”¹ Lisanti and colleagues have previously proposed an alternative model called the “the reverse Warburg effect,” in which aerobic glycolysis predominantly occurs in stromal fibroblasts.² During this process, cancer cells secrete oxidative stress factors, such as hydrogen peroxide, into the tumor microenvironment, which induces autophagy. This leads to degradation of mitochondria (mitophagy) and elevated glycolysis in cancer-associated fibroblasts.³ Aerobic glycolysis results in the elevated production of pyruvate, ketone bodies and L-lactate, which can be utilized by cancer cells for anabolic growth and metastasis. At the molecular level, stromal fibroblasts lose expression of caveolin-1 and activate HIF-1a (Fig. 1), TGFβ and NFκB signaling.⁴ Stromal caveolin-1 expression predicts clinical outcome in breast cancer patients.⁵Open in a separate windowFigure 1. CTGF-mediated autophagy-senescence transition in tumor stroma promotes anabolic tumor growth and metastasis. Cancer cells secrete oxidative stress factors (H₂O₂) that induce autophagy in cancer-associated fibroblasts. Additionally, caveolin-1 (cav-1) loss leads to activation of connective tissue growth factor (CTGF) and HIF-1α that mediate autophagy and senescence in these stromal cells. This is called the autophagy-senescence transition (AST). AST leads to mitophagy and elevated glycolysis in cancer-associated fibroblasts. Aerobic glycolysis results in the elevated production of several nutrients (pyruvate, ketone bodies and L-lactate), which can be utilized by cancer cells for tumor growth and metastasis.In the June 15, 2012 issue of Cell Cycle, two studies by Capparelli et al. further validate the “autophagic tumor stroma model of cancer” described above, as well as identify novel mechanisms involved in this process.^6,7 Autophagy and senescence are induced by the same stimuli and are known to occur simultaneously in cells. In the first study, the authors hypothesize that the onset of senescence in the tumor stroma in response to autophagy/mitophagy contributes to mitochondrial dysfunction and aerobic glycolysis. In order to genetically validate this process of autophagy-senescence transition (AST) (Fig. 1), Capparelli et al. overexpressed several autophagy-promoting factors (BNIP3, cathepsin B, Beclin-1 and ATG16L1) in hTERT fibroblasts to constitutively induce autophagy. Autophagic fibroblasts lost caveolin-1 expression and displayed enhanced tumor growth and metastasis when co-injected with breast cancer cells in mice, without an increase in angiogenesis. In contrast, constitutive activation of autophagy in breast cancer cells inhibited in vivo tumor growth. Autophagic fibroblasts also showed mitochondrial dysfunction, increased production of nutrients (L-lactate and ketone bodies) and features of senescence (β-galactosidase activity and p21 activation). AST was also demonstrated in human breast cancer patient samples.⁷ In the second study, using a similar experimental approach, the authors evaluated the role of the TGFβ target gene, connective tissue growth factor (CTGF), in the induction of AST and aerobic glycolysis in cancer-associated fibroblasts. CTGF would be activated in the tumor stroma upon loss of caveolin-1. CTGF overexpression in fibroblasts induced autophagy/mitophagy, glycolysis and L-lactate production in a HIF-1α-dependent manner along with features of senescence and oxidative stress. CTGF overexpression in fibroblasts also promoted tumor growth when co-injected with breast cancer cells in mice (Fig. 1), independent of angiogenesis. As expected, CTGF overexpression in breast cancer cells inhibited tumor growth. CTGF is known to be involved in extracellular matrix synthesis; however, the effects of CTGF overexpression in fibroblasts and tumor cells were found to be independent of this function.⁶Overall, the authors have identified a novel mechanism by which CTGF promotes AST and aerobic glycolysis in cancer-associated fibroblasts. In turn, the stromal cells stimulate anabolic tumor growth and metastasis. The authors also genetically validate the two-compartment model of cancer metabolism, whereby autophagy genes and CTGF have differential effects in stromal cells and tumor cells. The current studies have several implications for cancer therapy. The finding that HIF-1 activation is necessary for the induction of autophagy and senescence downstream of caveolin-1 loss and CTGF activation in stromal fibroblasts is intriguing. Activation of HIF-1 in the hypoxic tumor microenvironment is known to promote tumor cell growth, survival and therapeutic resistance.⁸ Therefore, targeting HIF-1 has the potential to block tumor progression through dual inhibitory effects on hypoxic cancer cell growth and survival as well as the induction of autophagy in stromal fibroblasts. CTGF and AST in the tumor stroma could serve as biomarkers for predicting clinical outcome, therapy response and metastasis. The two-compartment model of tumor metabolism raises further questions regarding the use of antioxidants and autophagy inhibitors/inducers for cancer therapy. The use of these agents in the clinic should be carefully evaluated considering their differential effects on stromal cells and cancer cells.