Platelet-derived growth factor (PDGF) ligands and their receptors (PDGFRα and PDGFRβ) regulate mesenchymal cells, such as fibroblasts and pericytes. These cells are important constituents of tumor ...stroma where they impact on tumor growth, metastasis and drug response.
Studies in model systems have demonstrated ability of the PDGF system to regulate the tumor-stimulatory effects of fibroblasts, as well as their ability to promote cancer cell migration and invasion. Animal studies imply PDGFR-signaling as a regulator of tumor drug uptake.
Emerging correlative analyses of different tumor collections are identifying clinically relevant variations in stromal PDGFR status, and associations between PDGFR status in tumor stroma and survival. These associations could either relate to effects of stromal PDGFR signaling on the natural course of the disease or response to treatment.
The availability of clinically approved PDGFR-inhibitory drugs suggest interesting possibilities for novel clinical studies, performed on selected patient sub-groups, which further exploits tumor stroma-derived PDGFR signaling.
Regulatory roles of stromal PDGF receptors. In most common cancer types PDGFRβ is expressed, at variable levels, in cancer-associated fibroblasts (starshaped cells) and perivascular cells. PDGFRα is predominantly detected in cancer-associated fibroblasts. Mechanistic studies have identified diverse effects of PDGFR signaling, or PDGFR positive cells, as summarized in the Table. Asterisk (*) indicate the existence of correlative data from analyses of clinical samples compatible with the mechanisms implied from experimental studies. Display omitted
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
A better understanding of mechanisms involved in regulation of drug sensitivity is crucial for improved cancer treatment. New studies show that cells of the tumor microenvironment modulate the ...response of cancer cells to chemotherapy and targeted therapies through production of secreted factors.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Ten years ago, Hanahan and Weinberg delineated six “Hallmarks of cancer” which summarize several decades of intense cancer research. However, tumor cells do not act in isolation, but rather subsist ...in a rich microenvironment provided by resident fibroblasts, endothelial cells, pericytes, leukocytes, and extra-cellular matrix. It is increasingly appreciated that the tumor stroma is an integral part of cancer initiation, growth and progression. The stromal elements of tumors hold prognostic, as well as response-predictive, information, and abundant targeting opportunities within the tumor microenvironment are continually identified. Herein we review the current understanding of tumor cell interactions with the tumor stroma with a particular focus on cancer-associated fibroblasts and pericytes. Moreover, we discuss emerging fields of research which need to be further explored in order to fulfil the promise of stroma-targeted therapies for cancer.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
PDGFs and their cognate tyrosine kinase α- and β-receptors are involved in multiple tumor-associated processes including autocrine growth stimulation of tumor cells, stimulation of tumor angiogenesis ...and recruitment and regulation of tumor fibroblasts. The recent development of clinically useful PDGF antagonists, like STI571/Glivec, has increased the interest in PDGF receptors as cancer drug targets. Autocrine PDGF receptor signaling occurs in certain malignancies characterized by mutational activation of PDGF or PDGF receptors, for instance, dermatofibrosaracoma protuberans, gastrointestinal stromal tumors, and hypereosinophilic syndrome. The roles of PDGF in regulation of tumor angiogenesis and tumor fibroblasts are more general, and probably occur in most common solid tumors. Concerning tumor angiogenesis recent studies have predominantly focused on the importance of PDGF receptor signaling for tumor pericyte recruitment. PDGF receptors in the tumor stroma have also attracted attention as interesting drug targets because of their function as regulators of tumor interstitial fluid pressure, tumor transvascular transport and tumor drug uptake. In summary, the improved understanding of the role of PDGF signaling in tumor biology, and the introduction of PDGF antagonists, has set the stage for a continued development of PDGF antagonists as novel cancer drugs.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Novel mechanisms, and molecular mediators, of the pro-tumorigenic effects of cancer-associated fibroblasts (CAFs) have been identified. These include CXCL12/SDF-1-mediated recruitment of bone ...marrow-derived endothelial precursor cell and pro-metastatic effects of CCL5. Co-culture experiments also suggest that CAFs can influence the drug-sensitivity of cancer cells. Comparisons of CAFs from different tumors have started to identify tumor-type specific differences in CAF gene expression and marker protein profiling indicates the existence of multiple distinct co-existing CAF-subsets. Studies in animal models have demonstrated that CAFs can be derived from bone marrow-derived cells or from epithelial or endothelial cells undergoing mesenchymal transition. The genetic status of CAFs remains controversial following conflicting findings. Meanwhile, analyses of CAFs from human tumors have revealed consistent epigenetic changes. An increasing number of translational studies have emphasized the prognostic significance of different CAF-related tumor characteristics. Clinical studies aiming at CAF-targeting can now be envisioned based on findings from experimental intervention studies with agents targeting, for example FAP or PDGF-, TGF-β- or hedgehog-signaling.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Cancer-associated fibroblasts (CAFs) are a heterogeneous cell population recognized as a key component of the tumour microenvironment (TME). Cancer-associated fibroblasts are known to play an ...important role in maintaining and remodelling the extracellular matrix (ECM) in the tumour stroma, supporting cancer progression and inhibiting the immune system’s response against cancer cells. This review aims to summarize the immunomodulatory roles of CAFs, particularly focussing on their T-cell suppressive effects. Cancer-associated fibroblasts have several ways by which they can affect the tumour’s immune microenvironment (TIME). For example, their interactions with macrophages and dendritic cells (DCs) create an immunosuppressive milieu that can indirectly affect T-cell anticancer immunity and enable immune evasion. In addition, a number of recent studies have confirmed CAF-mediated direct suppressive effects on T-cell anticancer capacity through ECM remodelling, promoting the expression of immune checkpoints, cytokine secretion and the release of extracellular vesicles. The consequential impact of CAFs on T-cell function is then reflected in affecting T-cell proliferation and apoptosis, migration and infiltration, differentiation and exhaustion. Emerging evidence highlights the existence of specific CAF subsets with distinct capabilities to modulate the immune landscape of TME in various cancers, suggesting the possibility of their exploitation as possible prognostic biomarkers and therapeutic targets.
Many solid tumours show an increased interstitial fluid pressure (IFP), which forms a barrier to transcapillary transport. This barrier is an obstacle in tumour treatment, as it results in ...inefficient uptake of therapeutic agents. There are a number of factors that contribute to increased IFP in the tumour, such as vessel abnormalities, fibrosis and contraction of the interstitial matrix. Lowering the tumour IFP with specific signal-transduction antagonists might be a useful approach to improving anticancer drug efficacy.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
PDGF receptors (PDGFRs) exert cell type-specific effects in many different tumor types. They are emerging as key regulators of mesenchymal cells of the tumor microenvironment, and of many common ...malignancies, such as cancer of the breast, colon and prostate. In some tumor types PDGFRs are genetically activated and are thus directly involved in stimulation of malignant cell growth. Recent studies have uncovered clinically relevant variations in stromal PDGFR expression. High stromal PDGFRβ expression or activation is associated with poor prognosis in breast and prostate cancer. Indications of prognostic significance of stromal PDGFRβ expression in various GI tract tumor types also exist. The prognostic significance of PDGFRα and β in malignant cells of common epithelial tumor types should be further studied. Collectively data suggest that continued characterization of PDGFR expression in human tumors should present opportunities for improved accuracy in prognosis and also allow novel biomarker-based clinical studies exploring the efficacy of PDGFR-directed tumor therapies.
Oxidation of the catalytic cysteine of protein-tyrosine phosphatases (PTP), which leads to their reversible inactivation, has emerged as an important regulatory mechanism linking cellular tyrosine ...phosphorylation and signalling by reactive-oxygen or -nitrogen species (ROS, RNS). This review focuses on recent findings about the involved pathways, enzymes and biochemical mechanisms. Both the general cellular redox state and extracellular ligand-stimulated ROS production can cause PTP oxidation. Members of the PTP family differ in their intrinsic susceptibility to oxidation, and different types of oxidative modification of the PTP catalytic cysteine can occur. The role of PTP oxidation for physiological signalling processes as well as in different pathologies is described on the basis of well-investigated examples. Criteria to establish the causal involvement of PTP oxidation in a given process are proposed. A better understanding of mechanisms leading to selective PTP oxidation in a cellular context, and finding ways to pharmacologically modulate these pathways are important topics for future research.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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