Diagnosis and treatment of disease demand a sound understanding of the underlying mechanisms, determining any Achilles' heel that can be targeted in effective therapies. Throughout history, this ...endeavour to decipher the origin and mechanism of transformation of a normal cell into cancer has led to various theories-from cancer as a curse to an understanding at the level of single-cell heterogeneity, meaning even among a single sub-type of cancer there are myriad molecular challenges to overcome. With increasing insight into cancer genetics and biology, the disease has become ever more complex to understand. The complexity of cancer as a disease was distilled into key traits by Hanahan and Weinberg in their seminal 'Hallmarks of Cancer' reviews. This lucid conceptualization of complex cancer biology is widely accepted and has helped advance cancer therapeutics by targeting the various hallmarks but, with the advancement in technologies, there is greater granularity in how we view cancer as a disease, and the additional understanding over the past decade requires us to revisit the hallmarks of cancer. Based on extensive study of the cancer research literature, we propose four novel hallmarks of cancer, namely, the ability of cells to regress from a specific specialized functional state, epigenetic changes that can affect gene expression, the role of microorganisms and neuronal signalling, to be included in the hallmark conceptualization along with evidence of various means to exploit them therapeutically.
The fibroblast growth factor (FGF) signalling pathway contributes to the regulation of a multitude of cellular functions, impacting on proliferation, survival, differentiation and migration. This ...biological importance is reflected by its prominent role in carcinogenesis; often being hijacked by cancer cells to offer growth or survival advantage. FGF signalling can contribute a driving force in the malignancy of different cancer types; through alterations in ligands, receptors or regulatory molecules. The dramatic advances in genomics technologies have highlighted how mutation, amplification, translocation or loss of elements in the FGF signalling network can contribute to cancer. Added to this are the stromal influences of FGF signalling. Dissection of the mechanisms that underlie the pro-tumourigenic effects resulting from perturbations to the FGF signalling network will be of utmost importance to the development of therapeutic approaches to treat FGF receptor (FGFR)-driven cancers. In this review, we will focus on the mechanisms of FGF deregulation, the prevalence of aberrations in different cancer types, and how we are progressing in the development of targeted therapies.
The pleiotropic effects of fibroblast growth factors (FGFs), the widespread expression of all seven signalling FGF receptors (FGFRs) throughout the body, and the dramatic phenotypes shown by many ...FGF/R knockout mice, highlight the diversity, complexity and functional importance of FGFR signalling. The FGF/R axis is critical during normal tissue development, homeostasis and repair. Therefore, it is not surprising that substantial evidence also pinpoints the involvement of aberrant FGFR signalling in disease, including tumourigenesis. FGFR aberrations in cancer include mutations, gene fusions, and amplifications as well as corrupted autocrine/paracrine loops. Indeed, many clinical trials on cancer are focusing on targeting the FGF/FGFR axis, using selective FGFR inhibitors, nonselective FGFR tyrosine kinase inhibitors, ligand traps, and monoclonal antibodies and some have already been approved for the treatment of cancer patients. The heterogeneous tumour microenvironment and complexity of FGFR signalling may be some of the factors responsible for the resistance or poor response to therapy with FGFR axis-directed therapeutic agents. In the present review we will focus on the structure and function of FGF(R)s, their common irregularities in cancer and the therapeutic value of targeting their function in cancer.
Highlights • We review the latest data on cellular fibroblast growth factor receptor (FGFR) signalling mechanisms and pathways. • We highlight key roles of FGFR signalling in normal development and ...repair. • We address how, and how often, it can go wrong in development and cancer. • We review the latest data on how FGFR signalling is being targeted therapeutically.
Cancers have a complex relationship with the surrounding environment that regulates everything from progression to response to treatment. Cell-cell and cell-matrix interactions are heavily influenced ...by protease biology. Studies on the tumor microenvironment have revealed a new complexity for proteases, describing novel substrates for classic proteases, and protease-independent roles for these enzymes. The rapid expansion of 3D in vitro model systems provides excellent tools to study the intricate influence of proteases on the tumor microenvironment. Here we describe a spheroid invasion assay, providing a platform to interrogate key protease-matrix interactions in the context of early-stage breast cancer. Incorporation of pharmacological inhibition and RNAi techniques enables the elucidation of key protease-dependent pathways and can be complemented with immunofluorescence analysis to visualize matrix cleavage events and visualize cell behavior during collective cell invasion.
The Obscure Potential of AHNAK2 Zardab, Mohamed; Stasinos, Konstantinos; Grose, Richard P ...
Cancers,
01/2022, Letnik:
14, Številka:
3
Journal Article
Recenzirano
Odprti dostop
AHNAK2 is a protein discovered in 2004, with a strong association with oncogenesis in various epithelial cancers. It has a large 616 kDa tripartite structure and is thought to take part in the ...formation of large multi-protein complexes. High expression is found in clear cell renal carcinoma, pancreatic ductal adenocarcinoma, uveal melanoma, and lung adenocarcinoma, with a relation to poor prognosis. Little work has been done in exploring the function and relation AHNAK2 has with cancer, with early studies showing promising potential as a future biomarker and therapeutic target.
Pancreatic cancer is characterised by desmoplasia, driven by activated pancreatic stellate cells (PSCs). Over‐expression of FGFs and their receptors is a feature of pancreatic cancer and correlates ...with poor prognosis, but whether their expression impacts on PSCs is unclear. At the invasive front of human pancreatic cancer, FGF2 and FGFR1 localise to the nucleus in activated PSCs but not cancer cells. In vitro, inhibiting FGFR1 and FGF2 in PSCs, using RNAi or chemical inhibition, resulted in significantly reduced cell proliferation, which was not seen in cancer cells. In physiomimetic organotypic co‐cultures, FGFR inhibition prevented PSC as well as cancer cell invasion. FGFR inhibition resulted in cytoplasmic localisation of FGFR1 and FGF2, in contrast to vehicle‐treated conditions where PSCs with nuclear FGFR1 and FGF2 led cancer cells to invade the underlying extra‐cellular matrix. Strikingly, abrogation of nuclear FGFR1 and FGF2 in PSCs abolished cancer cell invasion. These findings suggest a novel therapeutic approach, where preventing nuclear FGF/FGFR mediated proliferation and invasion in PSCs leads to disruption of the tumour microenvironment, preventing pancreatic cancer cell invasion.
Synopsis
Chemical or RNAi‐mediated inhibition of nuclear FGFR1 and FGF2 leads to disruption of the tumour‐supportive microenvironment provided by pancreatic stellate cells thus preventing pancreatic cancer cell invasion.
Nuclear FGFR1 and FGF2 are apparent in the stromal fibroblasts at the invasive front of human pancreatic cancer.
In vitro FGFR1 and FGF2 co‐localise to the nucleus in pancreatic stellate cells but not pancreatic cancer cells and are essential for proliferation and invasion.
Blocking nuclear FGFR1 and FGF2 results in a significant reduction in proliferation of pancreatic stellate cells and has a significant effect on invasion of pancreatic cancer cells in a 3D organotypic model of pancreatic cancer.
Chemical or RNAi‐mediated inhibition of nuclear FGFR1 and FGF2 leads to disruption of the tumour‐supportive microenvironment provided by pancreatic stellate cells thus preventing pancreatic cancer cell invasion.
The Future of Precision Oncology Rulten, Stuart L; Grose, Richard P; Gatz, Susanne A ...
International journal of molecular sciences,
08/2023, Letnik:
24, Številka:
16
Journal Article
Recenzirano
Odprti dostop
Our understanding of the molecular mechanisms underlying cancer development and evolution have evolved rapidly over recent years, and the variation from one patient to another is now widely ...recognized. Consequently, one-size-fits-all approaches to the treatment of cancer have been superseded by precision medicines that target specific disease characteristics, promising maximum clinical efficacy, minimal safety concerns, and reduced economic burden. While precision oncology has been very successful in the treatment of some tumors with specific characteristics, a large number of patients do not yet have access to precision medicines for their disease. The success of next-generation precision oncology depends on the discovery of new actionable disease characteristics, rapid, accurate, and comprehensive diagnosis of complex phenotypes within each patient, novel clinical trial designs with improved response rates, and worldwide access to novel targeted anticancer therapies for all patients. This review outlines some of the current technological trends, and highlights some of the complex multidisciplinary efforts that are underway to ensure that many more patients with cancer will be able to benefit from precision oncology in the near future.
Whilst cross-talk between stroma and epithelium is critical for tissue development and homeostasis, aberrant paracrine stimulation can result in neoplastic transformation. Chronic stimulation of ...epithelial cells with paracrine Fibroblast Growth Factor 10 (FGF10) has been implicated in multiple cancers, including breast, prostate and pancreatic ductal adenocarcinoma. Here, we examine the mechanisms underlying FGF10-induced tumourigenesis and explore novel approaches to target FGF10 signaling in cancer.
FGFR signalling in women's cancers Fearon, Abbie E.; Gould, Charlotte R.; Grose, Richard P.
The international journal of biochemistry & cell biology,
12/2013, Letnik:
45, Številka:
12
Journal Article
Recenzirano
FGFs, in a complex with their receptors (FGFRs) and heparan sulfate (HS), are responsible for a range of cellular functions, from embryogenesis to metabolism. Both germ line and somatic FGFR ...mutations are known to play a role in a range of diseases, most notably craniosynestosis dysplasias, dwarfism and cancer. Because of the ability of FGFR signalling to induce cell proliferation, migration and survival, FGFRs are readily co-opted by cancer cells. Mutations in, and amplifications of, these receptors are found in a range of cancers with some of the most striking clinical findings relating to their contribution to pathogenesis and progression of female cancers. Here, we outline the molecular mechanisms of FGFR signalling and discuss the role of this pathway in women's cancers, focusing on breast, endometrial, ovarian and cervical carcinomas, and their associated preclinical and clinical data. We also address the rationale for therapeutic intervention and the need for FGFR-targeted therapy to selectively target cancer cells in view of the fundamental roles of FGF signalling in normal physiology.
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