HSF1 is the major heat shock transcriptional factor that binds heat shock element (HSE) in the promoter of heat shock proteins (Hsps) and controls rapid Hsp induction in cells subjected to various environmental stresses. Although at least four members of the vertebrate HSF family have been described, details of their individual physiological roles remain relatively obscure. To assess whether HSF1 exhibited redundant or unique in vivo functions, we created Hsf1 -/-deficient mice. We demonstrate that homozygous Hsf1 -/-mice can survive to adulthood but exhibit multiple phenotypes including: defects of the chorioallantoic placenta and prenatal lethality; growth retardation; female infertility; elimination of the 'classical' heat shock response; and exaggerated tumor necrosis factor alpha production resulting in increased mortality after endotoxin challenge. Because basal Hsp expression is not altered appreciably by the HSF1 null mutation, our findings suggest that this factor, like Drosophila Hsf protein, might be involved in regulating other important genes or signaling pathways. Our results establish direct causal effects for the HSF1 transactivator in regulating critical physiological events during extraembryonic development and under pathological conditions such as sepsis to modulate pro-inflammatory responses, indicating that these pathways have clinical importance as therapeutic targets in humans.
The reception and integration of the plethora of signals a cell receives from its microenvironment determines the cell's fate. CD44 functions as a receptor for hyaluronan and many other extracellular matrix components, as well as a cofactor for growth factors and cytokines, and thus, CD44 is a signaling platform that integrates cellular microenvironmental cues with growth factor and cytokine signals and transduces signals to membrane-associated cytoskeletal proteins or to the nucleus to regulate a variety of gene expression levels related to cell-matrix adhesion, cell migration, proliferation, differentiation, and survival. Accumulating evidence indicates that CD44, especially CD44v isoforms, are cancer stem cell (CSC) markers and critical players in regulating the properties of CSCs, including selfrenewal, tumor initiation, metastasis, and chemoradioresistance. Furthermore, there is ample evidence that CD44, especially CD44v isoforms, are valuable prognostic markers in various types of tumors. Therefore, therapies that target CD44 may destroy the CSC population, and this holds great promise for the cure of life-threatening cancers. However, many challenges remain to determining how best to use CD44 as a biomarker and therapeutic target. Here we summarize the current findings concerning the critical role of CD44/CD44v in the regulation of cancer stemness and the research status of CD44/CD44v as biomarkers and therapeutic targets in cancer. We also discuss the current challenges and future directions that may lead to the best use of CD44/CD44v for clinical applications. STEM CELLS TRANSLATIONAL MEDICINE 2015;4:1033-1043 SIGNIFICANCEMounting evidence indicates that cancer stem cells (CSCs) are mainly responsible for cancer aggressiveness, drug resistance, and tumor relapse. CD44, especially CD44v isoforms, have been identified as CSC surface markers for isolating and enriching CSCs in different types of cancers. The current findings concerning the critical role of CD44/CD44v in regulation of cancer stemness and the research status of CD44/CD44v as biomarkers and therapeutic targets in cancer are summarized. The current challenges and future directions that may lead to best use of CD44/CD44v for clinical applications are also discussed.
Cancers with dysfunctional mutations in BRCA1 or BRCA2, most commonly associated with some breast cancers, are deficient in the DNA damage repair pathway called homologous recombination (HR), which makes them exquisitely vulnerable to poly(ADP-ribose) polymerase (PARP) inhibitors, such as olaparib. This functional state and therapeutic sensitivity is referred to as “BRCAness”. Pharmaceutical induction of BRCAness could expand the use of PARP inhibitors to other tumor types. For example, BRCA mutations are present in only a small proportion of prostate cancer (PCa) patients. We found that castration-resistant PCa (CRPC) cells increased expression of a set of HR-associated genes, including BRCA1, RAD54L and RMI2. Androgen-targeted therapy is typically not effective in CRPC patients. However, the androgen receptor (AR) inhibitor enzalutamide suppressed the expression of those HR genes, thus creating HR deficiency and BRCAness in CRPC cells. In a manner dependent on these gene expression effects, a “lead-in” treatment strategy, in which enzalutamide was followed by the combination of enzalutamide and olaparib, promoted DNA damage-induced cell death and inhibited clonal proliferation of PCa cells in culture and suppressed the growth of PCa xenografts in mice. Thus, our study suggests that anti-androgen and PARP inhibitor combination therapy may be effective for patients with CRPC, and that pharmaceutically-induced BRCAness may expand the clinical use of PARP inhibitors.
SUMMARY Understanding the molecular mechanisms of tumor initiation has significant impact on cancer early detection and intervention. To define the role of KLF4 in pancreatic ductal adenocarcinoma initiation, we used molecular biological analyses and mouse models of klf4 gain- and loss-of-function and mutant Kras. KLF4 is upregulated in and required for acinar-to-ductal metaplasia. Klf4 ablation drastically attenuates the formation of pancreatic intraepithelial neoplasia induced by mutant KrasG12D, whereas upregulation of KLF4 does the opposite. Mutant KRAS and cellular injuries induce KLF4 expression, and ectopic expression of KLF4 in acinar cells reduces acinar lineage- and induces ductal lineage-related marker expression. These results demonstrate that KLF4 induces ductal identity in PanIN initiation and may be a potential target for prevention of PDA initiation.
Solid tumors are composed of mutually interacting cancer cells and tumor microenvironment. Many environmental components, such as extracellular matrix (ECM), mesenchymal stem cells, endothelial and immune cells, and various growth factors and cytokines, provide signals, either stimulatory or inhibitory, to cancer cells and determine their fates. Meanwhile, cancer cells can also educate surrounding cells or tissues to undergo changes that are in favorable of tumor progression. CD44, as a transmembrane receptor for hyaluronic acid (HA) and many other ECM components and a coreceptor for growth factors and cytokines, is a critical cell surface molecule that can sense, integrate, and transduce cellular microenvironmental signals to membrane-associated cytoskeletal proteins or to cell nucleus to regulate a variety of gene expressions that govern cell behaviors. Mounting evidence suggests that CD44, particularly CD44v isoforms, are cancer stem cell (CSC) markers and critical regulators of cancer stemness, including self-renewal, tumor initiation, and metastasis. Thus, CD44 is widely used alone or in combination with other cell surface markers to isolate or enrich CSCs through fluorescence-activated cell sorting of dissociated single cells that originate from the patient, xenograft tumor tissues, or tumor cell cultures. Sorted cells are cultured in a specialized culture medium for spheroid formation or inoculated into immunodeficient mice for the analysis of tumorigenic or metastatic potential. In this chapter, detailed experimental methods regarding CD44 tumor cell isolation, spheroid culture, and characterization will be described.
Peroxisome proliferator-activated receptor-delta (PPAR-δ), one of three members of the PPAR group in the nuclear receptor superfamily, is a ligand-activated transcription factor. PPAR-δ regulates important cellular metabolic functions that contribute to maintaining energy balance. PPAR-δ is especially important in regulating fatty acid uptake, transport, and β-oxidation as well as insulin secretion and sensitivity. These salutary PPAR-δ functions in normal cells are thought to protect against metabolic-syndrome-related diseases, such as obesity, dyslipidemia, insulin resistance/type 2 diabetes, hepatosteatosis, and atherosclerosis. Given the high clinical burden these diseases pose, highly selective synthetic activating ligands of PPAR-δ were developed as potential preventive/therapeutic agents. Some of these compounds showed some efficacy in clinical trials focused on metabolic-syndrome-related conditions. However, the clinical development of PPAR-δ agonists was halted because various lines of evidence demonstrated that cancer cells upregulated PPAR-δ expression/activity as a defense mechanism against nutritional deprivation and energy stresses, improving their survival and promoting cancer progression. This review discusses the complex relationship between PPAR-δ in health and disease and highlights our current knowledge regarding the different roles that PPAR-δ plays in metabolism, inflammation, and cancer.
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