No abstract

Angiopoietin-like 4 (ANGPTL4) is best known for its role as an adipokine involved in the regulation of lipid and glucose metabolism. The characterization of ANGPTL4 as an adipokine is largely due to our limited understanding of the interaction partners of ANGPTL4 and how ANGPTL4 initiates intracellular signaling. Recent findings have revealed a critical role for ANGPTL4 in cancer growth and progression, anoikis resistance, altered redox regulation, angiogenesis, and metastasis. Emerging evidence suggests that ANGPTL4 function may be drastically altered depending on the proteolytic processing and posttranslational modifications of ANGPTL4, which may clarify several conflicting roles of ANGPTL4 in different cancers. Although the N-terminal coiled-coil region of ANGPTL4 has been largely responsible for the endocrine regulatory role in lipid metabolism, insulin sensitivity, and glucose homeostasis, it has now emerged that the COOH-terminal fibrinogen-like domain of ANGPTL4 may be a key regulator in the multifaceted signaling during cancer development. New insights into the mechanistic action of this functional domain have opened a new chapter into the possible clinical application of ANGPTL4 as a promising candidate for clinical intervention in the fight against cancer. This review summarizes our current understanding of ANGPTL4 in cancer and highlights areas that warrant further investigation. A better understanding of the underlying cellular and molecular mechanisms of ANGPTL4 will reveal novel insights into other aspects of tumorigenesis and the potential therapeutic value of ANGPTL4. Mol Cancer Res; 10(6); 677-88. Ó2012 AACR.

Histological inspection of visually normal tissue adjacent to neoplastic lesions often reveals multiple foci of cellular abnormalities. This suggests the presence of a regional carcinogenic signal that spreads oncogenic transformation and field cancerization. We observed an abundance of mutagenic reactive oxygen species in the stroma of cryosectioned patient tumor biopsies, indicative of extratumoral oxidative stress. Diffusible hydrogen peroxide (H2O2) was elevated in the conditioned medium of cultured skin epithelia at various stages of oncogenic transformation, and H2O2 production increased with greater tumor-forming and metastatic capacity of the studied cell lines. Explanted cancer-associated fibroblasts (CAFs) also had higher levels of H2O2 secretion compared with normal fibroblasts (FIBs). These results suggest that extracellular H2O2 acts as a field effect carcinogen. Indeed, H2O2-treated keratinocytes displayed decreased phosphatase and tensin homolog (PTEN) and increased Src activities because of oxidative modification. Furthermore, treating FIBs with CAF-conditioned medium or exogenous H2O2 resulted in the acquisition of an oxidative, CAF-like state. In vivo, the proliferative potential and invasiveness of composite tumor xenografts comprising cancerous or non-tumor-forming epithelia with CAFs and FIBs could be attenuated by the presence of catalase. Importantly, we showed that oxidatively transformed FIBs isolated from composite tumor xenografts retained their ability to promote tumor growth and aggressiveness when adoptively transferred into new xenografts. Higher H2O2 production by CAFs was contingent on impaired TGFβ signaling leading to the suppression of the antioxidant enzyme glutathione peroxidase 1 (GPX1). Finally, we detected a reduction in Smad3, TAK1 and TGFβRII expression in a cohort of 197 clinical squamous cell carcinoma (SCC) CAFs, suggesting that impaired stromal TGFβ signaling may be a clinical feature of SCC. Our study indicated that CAFs and cancer cells engage redox signaling circuitries and mitogenic signaling to reinforce their reciprocal relationship, suggesting that future anticancer approaches should simultaneously target ligand receptor and redox-mediated pathways.

Since the characterization of FABP5 in keratinocytes nearly two decades ago, numerous studies have demonstrated the expression of FABP5 in many tissues and organs, such as the epidermis, adipose tissue, mammary glands, brain, kidneys, liver, lungs, heart, skeletal muscles, and testes, as well as in specific cell types such as macrophages [16]. This expression pattern of FABP5 parallels that of PPARβ/δ in many of these tissues, and the interaction of FABP5 with PPARβ/δ is thought to affect many functions of PPARβ/δ, including those involving cellular glucose and lipid homeostasis, cell differentiation, and apoptotic resistance [15,17,18]. Indeed, cooperative activities between FABP5 and PPARβ/δ have been reported to be involved in neurogenesis [19] and in pathological conditions such as cancer [20,21], metabolic syndrome [22,23], and atherosclerosis [24]. 2.2 Transactivation and repression The transactivation of PPARβ/δ involves the binding of an agonist to the LBD of PPARβ/δ monomers or heterodimers with RXRs and the recruitment of coactivator molecules, such as CBP/p300 and other histone acetyltransferases [25-27] (Figure 1). However, in contrast to PPARα and PPARγ, PPARβ/δ functions as a transcriptional repressor in its unliganded state (Figure 1). This function of PPARβ/δ is attributed to two interrelated properties: unliganded PPARβ/δ is able to repress basal transcription as well as PPARα-and PPARγ-mediated transcription [28]. In that report, the authors demonstrated that unliganded PPARβ/δ suppressed basal transcription via the recruitment of corepressor molecules. They also demonstrated that PPARβ/δ induced isotype-specific repression of PPARα and PPARγ target genes through competition for the PPRE sites of those genes. It has also previously been shown that PPARβ/δ-Version postprint