Efforts to develop anti-cancer therapies have largely focused on targeting the epithelial compartment, despite the presence of non-neoplastic stromal components that substantially contribute to the ...progression of the tumor. Indeed, cancer cell survival, growth, migration, and even dormancy are influenced by the surrounding tumor microenvironment (TME). Within the TME, cancer-associated fibroblasts (CAFs) have been shown to play several roles in the development of a tumor. They secrete growth factors, inflammatory ligands, and extracellular matrix proteins that promote cancer cell proliferation, therapy resistance, and immune exclusion. However, recent work indicates that CAFs may also restrain tumor progression in some circumstances. In this review, we summarize the body of work on CAFs, with a particular focus on the most recent discoveries about fibroblast heterogeneity, plasticity, and functions. We also highlight the commonalities of fibroblasts present across different cancer types, and in normal and inflammatory states. Finally, we present the latest advances regarding therapeutic strategies targeting CAFs that are undergoing preclinical and clinical evaluation.
ROS in Cancer: The Burning Question Chio, Iok In Christine; Tuveson, David A
Trends in molecular medicine,
05/2017, Volume:
23, Issue:
5
Journal Article
Peer reviewed
Open access
An unanswered question in human health is whether antioxidation prevents or promotes cancer. Antioxidation has historically been viewed as chemopreventive, but emerging evidence suggests that ...antioxidants may be supportive of neoplasia. We posit this contention to be rooted in the fact that ROS do not operate as one single biochemical entity, but as diverse secondary messengers in cancer cells. This cautions against therapeutic strategies to increase ROS at a global level. To leverage redox alterations towards the development of effective therapies necessitates the application of biophysical and biochemical approaches to define redox dynamics and to functionally elucidate specific oxidative modifications in cancer versus normal cells. An improved understanding of the sophisticated workings of redox biology is imperative to defeating cancer.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Activated fibroblasts in tumors, or cancer-associated fibroblasts (CAFs), have become a popular research area over the past decade. As important players in many aspects of tumor biology, with ...functions ranging from collagen deposition to immunosuppression, CAFs have been the target of clinical and pre-clinical studies that have revealed their potential pro- and anti-tumorigenic dichotomy. In this review, we describe the important role of CAFs in the tumor microenvironment and the technological advances that made these discoveries possible, and we detail the models that are currently available for CAF investigation. Additionally, we present evidence to support the value of encompassing CAF investigation as a future therapeutic avenue alongside immune and cancer cells while highlighting the challenges that must be addressed for successful clinical translation of new findings.
Caligiuri and Tuveson discuss the most recent findings on cancer-associated fibroblasts and their role in primary and metastatic tumor sites. They summarize technological advances in pre-clinical modeling of cancer-associated fibroblasts as well as their clinical potential as therapeutic targets for cancer therapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
We recently proposed that competitive endogenous RNAs (ceRNAs) sequester microRNAs to regulate mRNA transcripts containing common microRNA recognition elements (MREs). However, the functional role of ...ceRNAs in cancer remains unknown. Loss of PTEN, a tumor suppressor regulated by ceRNA activity, frequently occurs in melanoma. Here, we report the discovery of significant enrichment of putative PTEN ceRNAs among genes whose loss accelerates tumorigenesis following Sleeping Beauty insertional mutagenesis in a mouse model of melanoma. We validated several putative PTEN ceRNAs and further characterized one, the ZEB2 transcript. We show that ZEB2 modulates PTEN protein levels in a microRNA-dependent, protein coding-independent manner. Attenuation of ZEB2 expression activates the PI3K/AKT pathway, enhances cell transformation, and commonly occurs in human melanomas and other cancers expressing low PTEN levels. Our study genetically identifies multiple putative microRNA decoys for PTEN, validates ZEB2 mRNA as a bona fide PTEN ceRNA, and demonstrates that abrogated ZEB2 expression cooperates with BRAFV600E to promote melanomagenesis.
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► A Sleeping Beauty screen followed by MuTaME analysis discovered putative PTEN ceRNAs ► The PTEN ceRNA ZEB2 regulates PTEN in a miRNA-dependent manner ► ZEB2 loss activates PI3K/AKT signaling and promotes cell transformation ► Attenuated ZEB2 expression is found in melanoma and other human cancers
A transposon-based mutagenesis screen uncovers a striking enrichment of putative PTEN ceRNAs among mutated genes that accelerate tumorigenesis in a mouse model of melanoma. One candidate gene, ZEB2, regulates PI3K/AKT signaling and tumor-suppressive properties of PTEN.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The Pancreas Cancer Microenvironment FEIG, Christine; GOPINATHAN, Aarthi; NEESSE, Albrecht ...
Clinical cancer research,
08/2012, Volume:
18, Issue:
16
Journal Article
Peer reviewed
Open access
Pancreatic ductal adenocarcinoma (PDA) is a common and lethal malignancy resulting in more than 250,000 deaths per year worldwide. Despite extensive efforts, cytotoxic and targeted therapies have ...provided only limited efficacy for patients with PDA to date. One contributing factor to the failure of systemic therapies may be the abundant tumor stromal content that is the characteristic of PDA. The PDA stroma, aptly termed the tumor microenvironment, occupies the majority of the tumor mass, and consists of a dynamic assortment of extracellular matrix components and nonneoplastic cells including fibroblastic, vascular, and immune cells. Recent work has revealed that the PDA stroma supports tumor growth and promotes metastasis and simultaneously serves as a physical barrier to drug delivery. Accordingly, methods that alter stromal composition or function, for instance interference with the vasculature via Notch/Hedgehog pathway inhibition or relief of vascular compression by hyaluronidase, are under active investigation. Here, we will review our current understanding of the PDA tumor microenvironment, and highlight opportunities for further exploration that may benefit patients.
Although metastasis is a major cause of morbidity and mortality in patients with pancreatic cancer, the requisite events are currently unknown. In this issue of Cell, Haeno et al. and Rhim et al. ...propose that metastasis occurs much earlier than previously anticipated, with clear implications for improving patient care.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Pancreatic ductal adenocarcinoma (PDA) exhibits one of the poorest prognosis of all solid tumours and poses an unsolved problem in cancer medicine. Despite the recent success of two combination ...chemotherapies for palliative patients, the modest survival benefits are often traded against significant side effects and a compromised quality of life. Although the molecular events underlying the initiation and progression of PDA have been intensively studied and are increasingly understood, the reasons for the poor therapeutic response are hardly apprehended. One leading hypothesis over the last few years has been that the pronounced tumour microenvironment in PDA not only promotes carcinogenesis and tumour progression but also mediates therapeutic resistance. To this end, targeting of various stromal components and pathways was considered a promising strategy to biochemically and biophysically enhance therapeutic response. However, none of the efforts have yet led to efficacious and approved therapies in patients. Additionally, recent data have shown that tumour-associated fibroblasts may restrain rather than promote tumour growth, reinforcing the need to critically revisit the complexity and complicity of the tumour-stroma with translational implications for future therapy and clinical trial design.
It has been proposed that reactive oxygen species (ROS) cause mutations, and thus cancer, and that antioxidants counter this effect, but studies suggest that antioxidants do not prevent cancer and ...may accelerate it. These findings may be due to the cellular location of ROS targeted by antioxidants.
Reactive oxygen species (ROS) have been proposed to both accelerate and delay cancer initiation and progression. These conflicting outcomes may be explained by the multiple roles that ROS play during the evolution of cancer cells.
ROS can promote cancer by oxidizing specific intracellular chemical moieties, resulting in genetic mutations and the activation of biochemical pathways that stimulate proliferation and neoplastic transformation.
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These tumorigenic properties of ROS have prompted the evaluation of dietary antioxidants as potential preventive and therapeutic agents in animal models and humans. Although some early preclinical studies supported this concept, dietary antioxidants have consistently failed to reduce the . . .
Despite being surrounded by diverse nutrients, mammalian cells preferentially metabolize glucose and free amino acids. Recently, Ras-induced macropinocytosis of extracellular proteins was shown to ...reduce a transformed cell’s dependence on extracellular glutamine. Here, we demonstrate that protein macropinocytosis can also serve as an essential amino acid source. Lysosomal degradation of extracellular proteins can sustain cell survival and induce activation of mTORC1 but fails to elicit significant cell accumulation. Unlike its growth-promoting activity under amino-acid-replete conditions, we discovered that mTORC1 activation suppresses proliferation when cells rely on extracellular proteins as an amino acid source. Inhibiting mTORC1 results in increased catabolism of endocytosed proteins and enhances cell proliferation during nutrient-depleted conditions in vitro and within vascularly compromised tumors in vivo. Thus, by preventing nutritional consumption of extracellular proteins, mTORC1 couples growth to availability of free amino acids. These results may have important implications for the use of mTOR inhibitors as therapeutics.
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•Ras-directed protein macropinocytosis is an essential amino acid source•Lysosomal degradation of extracellular proteins activates the mTORC1 pathway•mTORC1 suppresses lysosomal catabolism of proteins taken up from the environment•mTORC1 inhibition promotes growth of amino-acid-starved cells and hypovascular tumors
Unlike its growth-promoting activity under amino-acid-replete conditions, mTORC1 activation suppresses proliferation when cells rely on extracellular proteins as an amino acid source. Importantly, inhibiting mTORC1 increases cell proliferation during amino acid starvation within vascularly compromised tumor regions, which may have implications for the use of mTOR inhibitors as therapeutics for cancer.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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