There are currently no effective therapies for metastatic prostate cancer because the molecular mechanisms that underlie the metastatic spread of primary prostate cancer are unclear. Transcription factor Stat3 is constitutively active in malignant prostate epithelium, and its activation is associated with high histological grade and advanced cancer stage. Progression of prostate cancer to metastatic disease is one of the key problems in the clinical management of prostate cancer.1 This is because there are currently no effective therapies for metastatic prostate cancer, and metastatic prostate cancer is the lethal form of the disease. Identification of the molecular changes that lead to formation of distant metastasis is critical for improvement of therapeutic interventions for metastatic prostate cancer and for development of strategies to prevent primary prostate cancer from metastasizing.Transcription factor Stat3 has been implicated in the promotion of growth and progression of prostate cancer. Stat3, which is both a cytoplasmic signaling molecule and a nuclear transcription factor, belongs to the sevenmember Stat gene family of transcription factors.2 Stat3 becomes active by phosphorylation of a specific tyrosine residue in the carboxy-terminal domain by a tyrosine kinase (pY705).3 Activation of Stat3 is supplemented by phosphorylation of a specific serine residue (S727).4 After phosphorylation, Stat3 homodimerizes and translocates to the nucleus where it binds to specific Stat3 response elements of target gene promoters to regulate transcription.3 Transcription factor Stat3 is constitutively active in clinical human prostate cancer, 5-9 and activation of Stat3 has been associated with advanced stage of prostate cancer. 5,9 Moreover, several reports implicate Stat3 in promotion of prostate cancer cell proliferation and inhibition of apoptosis. 5,10,11
Senescent fibroblasts are known to promote tumor growth. However, the exact mechanism remains largely unknown. An important clue comes from recent studies linking autophagy with the onset of senescence. Thus, autophagy and senescence may be part of the same physiological process, known as the autophagy-senescence transition (AST). To test this hypothesis, human fibroblasts immortalized with telomerase (hTERT-BJ1) were stably transfected with autophagy genes (BNIP3, CTSB or ATG16L1). Their overexpression was sufficient to induce a constitutive autophagic phenotype, with features of mitophagy, mitochondrial dysfunction and a shift toward aerobic glycolysis, resulting in L-lactate and ketone body production. Autophagic fibroblasts also showed features of senescence, with increased p21(WAF1/CIP1), a CDK inhibitor, cellular hypertrophy and increased β-galactosidase activity. Thus, we genetically validated the existence of the autophagy-senescence transition. Importantly, autophagic-senescent fibroblasts promoted tumor growth and metastasis, when co-injected with human breast cancer cells, independently of angiogenesis. Autophagic-senescent fibroblasts stimulated mitochondrial metabolism in adjacent cancer cells, when the two cell types were co-cultured, as visualized by MitoTracker staining. In particular, autophagic ATG16L1 fibroblasts, which produced large amounts of ketone bodies (3-hydroxy-butyrate), had the strongest effects and promoted metastasis by up to 11-fold. Conversely, expression of ATG16L1 in epithelial cancer cells inhibited tumor growth, indicating that the effects of autophagy are compartment-specific. Thus, autophagic-senescent fibroblasts metabolically promote tumor growth and metastasis, by paracrine production of high-energy mitochondrial fuels. Our current studies provide genetic support for the importance of “two-compartment tumor metabolism” in driving tumor growth and metastasis via a simple energy transfer mechanism. Finally, β-galactosidase, a known lysosomal enzyme and biomarker of senescence, was localized to the tumor stroma in human breast cancer tissues, providing in vivo support for our hypothesis. Bioinformatic analysis of genome-wide transcriptional profiles from tumor stroma, isolated from human breast cancers, also validated the onset of an autophagy-senescence transition. Taken together, these studies establish a new functional link between host aging, autophagy, the tumor microenvironment and cancer metabolism.
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