Nature Reviews Cancer

Published by Springer Nature


Field effect
  • Article

July 2012


65 Reads

Sarah Seton-Rogers
The phenomenon of field cancerization (the existence of histologically abnormal tissue beyond a neoplastic area that predisposes to tumour formation) was described in the 1950s on the basis of analyses of squamous cell carcinomas (SCCs). Field cancerization is primarily attributed to changes in the epithelium, but whether changes in mesenchymal cells might also have a primary role in the establishment of afield effect is not clear.

Figure 1: Relative survival (5 year or 10 year) among cancer cases diagnosed with distant, regional or distant, and localized disease by year of diagnosis.a | Breast cancer; b | colorectal cancer; c | lung cancer; d | prostate cancer. Source: Surveillance, Epidemiology and End Results (SEER)1. Stage is SEER historic stage.
Table 1 | Projected changes in survival with early detection
Early detection: The case for early detection
  • Literature Review
  • Full-text available

May 2003


2,801 Reads






Early detection represents one of the most promising approaches to reducing the growing cancer burden. It already has a key role in the management of cervical and breast cancer, and is likely to become more important in the control of colorectal, prostate and lung cancer. Early-detection research has recently been revitalized by the advent of novel molecular technologies that can identify cellular changes at the level of the genome or proteome, but how can we harness these new technologies to develop effective and practical screening tests?

Deeb KK, Trump DL, Johnson CSVitamin D signalling pathways in cancer: Potential for anticancer therapeutics. Nat Rev Cancer 7: 684-700, doi: 10.1038/nrc.2196

October 2007


422 Reads

Epidemiological studies indicate that vitamin D insufficiency could have an aetiological role in various human cancers. Preclinical research indicates that the active metabolite of vitamin D, 1alpha,25(OH)2D3, also known as calcitriol, or vitamin D analogues might have potential as anticancer agents because their administration has antiproliferative effects, can activate apoptotic pathways and inhibit angiogenesis. In addition, 1alpha,25(OH)2D3 potentiates the anticancer effects of many cytotoxic and antiproliferative anticancer agents. Here, we outline the epidemiological, preclinical and clinical studies that support the development of 1alpha,25(OH)2D3 and vitamin D analogues as preventative and therapeutic anticancer agents.

Figure 1: Androgen action.Testosterone circulates in the blood bound to albumin (not shown) and sex-hormone-binding globulin (SHBG), and exchanges with free testosterone. Free testosterone enters prostate cells and is converted to dihydrotestosterone (DHT) by the enzyme 5-reductase. Binding of DHT to the androgen receptor (AR) induces dissociation from heat-shock proteins (HSPs) and receptor phosphorylation. The AR dimerizes and can bind to androgen-response elements in the promoter regions of target genes6. Co-activators (such as ARA70) and corepressors (not shown) also bind the AR complex, facilitating or preventing, respectively, its interaction with the general transcription apparatus (GTA). Activation (or repression) of target genes leads to biological responses including growth, survival and the production of prostate-specific antigen (PSA). Potential transcription-independent actions of androgens are not shown.
Table 1 | Mechanisms of development of AIPC
Figure 4: How growth factor signal transduction creates outlaw receptors.In the tumour cells of a patient receiving androgen ablation therapy, HER-2/neu (and possibly other receptor tyrosine kinases) can become overexpressed. HER-2/neu indirectly activates mitogen-activated protein kinase (MAPK). MAPK might phosphorylate the androgen receptor (AR), creating an androgen-independent 'outlaw' receptor. An alternative means by which HER-2/neu (or other pathways) might activate the AR is by activating the AKT (protein kinase B) pathway. In this pathway, activation of receptor tyrosine kinases, such as HER-2/neu, increase the level of phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P3) by activating phosphatidylinositol 3-kinase (PI3K). Another pathway might involve inactivation of the lipid phosphatase PTEN, so that PtdIns(3,4,5)P3 can no longer be converted back to its substrate, PtdIns(4,5)P2. AKT is activated by PtdIns(3,4,5)P3, and might be able to produce an outlaw AR by phosphorylating it. AKT can also activate parallel survival pathways by phosphorylating and inactivating pro-apoptotic molecules such as BAD and procaspase-9. ARE, androgen response element; PSA, prostate-specific antigen.
Feldman BJ, Feldman DThe development of androgen-independent prostate cancer. Nat Rev Cancer 1: 34-45. DOI: 10.1038/35094009

November 2001


7,103 Reads

The normal prostate and early-stage prostate cancers depend on androgens for growth and survival, and androgen ablation therapy causes them to regress. Cancers that are not cured by surgery eventually become androgen independent, rendering anti-androgen therapy ineffective. But how does androgen independence arise? We predict that understanding the pathways that lead to the development of androgen-independent prostate cancer will pave the way to effective therapies for these, at present, untreatable cancers.

Schvartzman JM, Sotillo R, Benezra R.. Mitotic chromosomal instability and cancer: mouse modelling of the human disease. Nat Rev Cancer 10: 102-115

February 2010


276 Reads

The stepwise progression from an early dysplastic lesion to full-blown metastatic malignancy is associated with increases in genomic instability. Mitotic chromosomal instability - the inability to faithfully segregate equal chromosome complements to two daughter cells during mitosis - is a widespread phenomenon in solid tumours that is thought to serve as the fuel for tumorigenic progression. How chromosome instability (CIN) arises in tumours and what consequences it has are still, however, hotly debated issues. Here we review the recent literature with an emphasis on models that recapitulate observations from human disease.

Yu, H. & Jove, R. The STATs of cancer - new molecular targets come of age. Nature Rev. Cancer 4, 97-105

March 2004


228 Reads

Tumour cells acquire the ability to proliferate uncontrollably, resist apoptosis, sustain angiogenesis and evade immune surveillance. STAT proteins — especially STAT3 and STAT5 — regulate all of these processes and are persistently activated in a surprisingly large number of human cancers. Consequently, STAT proteins are emerging — unexpectedly — as ideal targets for cancer therapy.

Jackson JR, Patrick DR, Dar MM, Huang PS.. Targeted anti-mitotic therapies: can we improve on tubulin agents? Nat Rev Cancer 7: 107-117
The advent of molecularly targeted drug discovery has facilitated the identification of a new generation of anti-mitotic therapies that target proteins with specific functions in mitosis. The exquisite selectivity for mitosis and the distinct ways in which these new agents interfere with mitosis provides the potential to not only overcome certain limitations of current tubulin-targeted anti-mitotic drugs, but to expand the scope of clinical efficacy that those drugs have established. The development of these new anti-mitotic drugs as targeted therapies faces significant challenges; nevertheless, these potential therapies also serve as unique tools to dissect the molecular mechanisms of the mitotic-checkpoint response.

Whibley C, Pharoah PD, Hollstein Mp53 polymorphisms: cancer implications. Nat Rev Cancer 9:95-107

February 2009


82 Reads

The normal functioning of p53 is a potent barrier to cancer. Tumour-associated mutations in TP53, typically single nucleotide substitutions in the coding sequence, are a hallmark of most human cancers and cause dramatic defects in p53 function. By contrast, only a small fraction, if any, of the >200 naturally occurring sequence variations (single nucleotide polymorphisms, SNPs) of TP53 in human populations are expected to cause measurable perturbation of p53 function. Polymorphisms in the TP53 locus that might have cancer-related phenotypical manifestations are the subject of this Review. Polymorphic variants of other genes in the p53 pathway, such as MDM2, which might have biological consequences either individually or in combination with p53 variants are also discussed.

Rice, J, Ottensmeier, CH and Stevenson, FK. DNA vaccines: precision tools for activating effective immunity against cancer. Nat Rev Cancer 8: 108-120
DNA vaccination has suddenly become a favoured strategy for inducing immunity. The molecular precision offered by gene-based vaccines, together with the facility to include additional genes to direct and amplify immunity, has always been attractive. However, the apparent failure to translate operational success in preclinical models to the clinic, for reasons that are now rather obvious, reduced initial enthusiasm. Recently, novel delivery systems, especially electroporation, have overcome this translational block. Here, we assess the development, current performance and potential of DNA vaccines for the treatment of cancer.

Figure 1: Cells are tuned to the materials properties of their matrix.All cells, including those in traditionally mechanically static tissues, such as the breast or the brain, are exposed to isometric force or tension that is generated locally at the nanoscale level by cell–cell or cell–extracellular matrix interactions and that influences cell function through actomyosin contractility and actin dynamics. Moreover, each cell type is specifically tuned to the specific tissue in which it resides. The brain, for instance, is infinitely softer than bone tissue. Consequently, neural cell growth, survival and differentiation are favoured by a highly compliant matrix. By contrast, osteoblast differentiation and survival occurs optimally on stiffer extracellular matrices with material properties more similar to newly formed bone. Normal mammary epithelial cell growth, survival, differentiation and morphogenesis are optimally supported by interaction with a soft matrix. Following transformation, however, breast tissue becomes progressively stiffer and tumour cells become significantly more contractile and hyper-responsive to matrix compliance cues. Normalizing the tensional homeostasis of tumour cells, however, can revert them towards a non-malignant phenotype6, thereby illustrating the functional link between matrix materials properties, cellular tension and normal tissue behaviour. Importantly, however, although breast tumours are much stiffer than the normal breast, the materials properties of a breast tumour remain significantly softer than those of muscle or bone, emphasizing the critical association between tissue phenotype and matrix rigidity.
Figure 2: Mechanotransduction and focal adhesion maturation.a | The majority of integrins exist at the plasma membrane in a resting, inactive state in which they can be activated by inside–out or outside–in cues. With regard to outside–in activation, when cells encounter a mechanically rigid matrix or are exposed to an exogenous force integrins become activated, which favours integrin oligomerization or clustering, talin 1 and p130Cas protein unfolding, vinculin–talin association, and Src and focal adhesion kinase (FAK) stimulation of RhoGTPase-dependent actomyosin contractility and actin remodelling. Focal adhesions mature with the recruitment of a repertoire of adhesion plaque proteins, including -actinin to facilitate actin association, and adaptor proteins such as paxillin, which foster interactions between multiple signalling complexes to promote growth, migration and differentiation. b | Normal cells tune their contractility in response to matrix stiffness cues, but tumours exhibit altered tensional homeostasis. Cells exert actomyosin contractility and cytoskeleton-dependent force in response to matrix stiffness cues. These forces can be measured using traction force microscopy. Thus, non-malignant human mammary epithelial cells spread more and exert more force on a stiff matrix than on a soft matrix. c | By comparison, breast tumour cells (T4) are highly contractile and spread considerably more than their non-malignant counterparts (S1) in response to the same compliant matrix. Importantly, inhibiting RhoGTPase signalling in tumour cells, by expressing a dominant-negative N19Rho or treating tumours with an inhibitor of Rho-associated, coiled-coil-containing protein kinase (ROCK; Y-27632) or myosin 2 (blebbistatin), reduces tumour cell contractility and spreading to levels exhibited by non-malignant breast epithelial cells. These data illustrate the importance of Rho signalling and actomyosin contractility in cell force generation and show how transformation alters cell force sensing. The traction map is shown in pseudocolour indicating regions of low (grey) and high (purple) forces in dynes per cm2. ECM, extracellular matrix; SFK, Src family kinase. Reproduced, with permission, from Ref. 6 © (2005) Elsevier Inc.
Figure 3: The normal mammary gland as a mechanically active tissue.a | The developing breast is subjected to a number of forces that facilitate its normal function. During lactation, for instance, the normal breast experiences compressive stress on the luminal epithelial cells and the basement membrane owing to the accumulation of milk and alveolar distension. Upon sucking and oxytocin stimulation, epithelial cells encounter inward tensile stress as the myoepithelium contracts to force the milk out of the alveolar sacs. In the absence of this stimulus, milk will accumulate within the acinus and eventually exert an outward projecting compressive force on the surrounding epithelium. This compressive force is countered by a compensatory inward projecting resistance force and the combination of these two forces eventually compromises the integrity of the tight junctions between alveolar cells. Chronic exposure to these forces and perturbed tissue integrin sensitize the gland to apoptotic cues so that the gland undergoes involution accompanied by extensive remodelling of the epithelium and the cellular and extracellular components of the stroma. b | Transformation (blue cells) resulting from the accumulation of genetic and epigenetic alterations in the epithelium along with an altered stromal matrix leads to unchecked proliferation and enhanced survival of luminal epithelial cells within the ductal tree, which compromises normal ductal architecture. With prolonged growth and abnormal survival, the abnormal pre-neoplastic luminal mammary epithelial cells eventually expand to fill the breast ducts. The expanding luminal epithelial mass exerts outward projecting compression forces of increasing magnitude on the basement membrane and adjacent myoepithelium. These forces are countered by an inward projecting resistance force. Importantly, the pre-neoplastic lesion secretes a plethora of soluble factors that stimulate immune cell infiltration and activation of resident fibroblasts to induce a desomoplastic response in the breast stroma. The desmoplastic stroma, which is characterized by dramatic changes in the composition, post-translational modifications and topology of the extracellular matrix (ECM), stiffens over time. This rigid parenchyma exerts a progressively greater inward projecting resistance force on the expanding pre-neoplastic duct. Over time, the number of myoepithelial cells surrounding the pre-neoplastic mass decreases and the basement membrane thins, probably owing to increased matrix metalloproteinase (MMP) activity, decreased protein deposition and compromised assembly (adapted from Ref. 128). In parallel, there is a build-up of interstitial fluid pressure contributed by a leaky vasculature and compromised lymphatic drainage. In response to their genetic modifications and the altered materials properties of the matrix, the pre-neoplastic luminal epithelial cells exhibit modified tensional homeostasis and respond to the combination of forces and stromal cues to invade the breast parenchyma. Some resident fibroblasts transdifferentiate into myofibroblasts and facilitate tumour migration and invasion by promoting the assembly of linearized collagen fibrils surrounding the distended pre-neoplastic epithelial ducts.
Figure 5: Imaging elastography of a breast tumour.Tissue imaging elastography is a spatial 'visual' qualitative measurement of the stiffness of a tissue that is generated by extrapolating tissue viscoelastic characteristics from ultrasound wave reflection in real-time. Photographs of sonoelastography images compare an elastogram image (a) with a B mode ultrasound scan (b) of a breast tumour170. Ultrasound imaging elastography, as shown here, is an in situ mechanical imaging method that could improve the sensitivity and the specificity of breast cancer detection and may be a useful tool to advance our understanding of the link between mammographic density and the matrix materials properties of the breast. Image courtesy of A. Thomas & T. Fischer, Charité, Berlin, Germany.
Butcher DT, Alliston T, Weaver VM.. A tense situation: forcing tumour progression. Nat Rev Cancer 9: 108-122
Cells within tissues are continuously exposed to physical forces including hydrostatic pressure, shear stress, and compression and tension forces. Cells dynamically adapt to force by modifying their behaviour and remodelling their microenvironment. They also sense these forces through mechanoreceptors and respond by exerting reciprocal actomyosin- and cytoskeletal-dependent cell-generated force by a process termed 'mechanoreciprocity'. Loss of mechanoreciprocity has been shown to promote the progression of disease, including cancer. Moreover, the mechanical properties of a tissue contribute to disease progression, compromise treatment and might also alter cancer risk. Thus, the changing force that cells experience needs to be considered when trying to understand the complex nature of tumorigenesis.

Jallepalli PV, Lengauer C.. Chromosome segregation and cancer: cutting through the mystery. Nat Rev Cancer 1: 109-117

December 2001


105 Reads

Mitosis is the most dramatic--and potentially dangerous--event in the cell cycle, as sister chromatids are irreversibly segregated to daughter cells. Defects in the checkpoints that normally maintain the fidelity of this process can lead to chromosomal instability (CIN) and cancer. However, CIN--a driving force of tumorigenesis--could be the cancer cell's ultimate vulnerability. An important goal is to identify novel anticancer compounds that directly target the mitotic errors at the heart of CIN.

Hitzler, J.K. & Zipursky, A. A. Origins of leukaemia in children with Down syndrome. Nat. Rev. Cancer 5, 11-20

February 2005


72 Reads

Transient megakaryoblastic leukaemia is found in 10% of newborns with Down syndrome, characterized by constitutional trisomy 21. Although in most cases the leukaemic cells disappear spontaneously after the first months of life, irreversible acute megakaryoblastic leukaemia develops in 20% of these individuals within 4 years. The leukaemic cells typically harbour somatic mutations of the gene encoding GATA1, an essential transcriptional regulator of normal megakaryocytic differentiation. Leukaemia that specifically arises in the context of constitutional trisomy 21 and somatic GATA1 mutations is a unique biological model of the incremental process of leukaemic transformation.

Wouters BG, Koritzinsky MHypoxia signalling through mTOR and the unfolded protein response in cancer. Nat Rev Cancer 8(11): 851-864

November 2008


1,595 Reads

Hypoxia occurs in the majority of tumours, promoting angiogenesis, metastasis and resistance to therapy. Responses to hypoxia are orchestrated in part through activation of the hypoxia-inducible factor family of transcription factors (HIFs). Recently, two additional O(2)-sensitive signalling pathways have also been implicated: signalling through the mammalian target of rapamycin (mTOR) kinase and signalling through activation of the unfolded protein response (UPR). Although they are activated independently, growing evidence suggests that HIF-, mTOR- and UPR-dependent responses to hypoxia act in an integrated way, influencing each other and common downstream pathways that affect gene expression, metabolism, cell survival, tumorigenesis and tumour growth.

Rowland BD, Peeper DS.. KLF4, p21 and context-dependent opposing forces in cancer. Nat Rev Cancer 6: 11-23

February 2006


107 Reads

Krüppel-like factors are transcriptional regulators that influence several cellular functions, including proliferation. Recent studies have shown that one family member, KLF4, can function both as a tumour suppressor and an oncogene. The ability of KLF4 to affect the levels of expression of the cell-cycle regulator p21 seems to be involved, in that this protein might function as a switch that determines the outcome of KLF4 signalling. Is this role of p21 restricted to KLF4, or does p21 represent a nodal point for signals from multiple other factors with opposing functions in cancer?

Figure 2: Non-canonical activities of ARSs and AIMPs implicated in the control of tumorigenesis.Eight different aminoacyl-tRNA synthetases (ARSs), bifunctional glutamyl-prolyl-tRNA synthetase (EPRS), isoleucyl-tRNA synthetase (IRS), leucyl-tRNA synthetase (LRS), methionyl-tRNA synthetase (MRS), glutaminyl-tRNA synthetase (QRS), lysyl-tRNA synthetase (KRS), aspartyl-tRNA synthetase (DRS) and arginyl-tRNA synthetase (RRS), form a macromolecular protein complex with three auxiliary factors, designated ARS-interacting multifunctional protein 1 (AIMP1), AIMP2 and AIMP3. This complex is known as the multisynthetase complex (MSC) and is shown in blue. Within the complex, RRS, KRS and MRS specifically interact with AIMP1, AIMP2 and AIMP3, respectively. On genotoxic damage, AIMP2 and AIMP3 are translocated to the nucleus where AIMP2 activates p53 directly36 and AIMP3 activates p53 through the activation of the kinases ataxia telangiectasia mutated (ATM) and ATM- and Rad3-related (ATR)40. AIMP2 also augments the apoptotic signal of tumour necrosis factor (TNF) through downregulation of TNF receptor associated factor 2 (TRAF2)34 and mediates the transforming growth factor-β (TGFβ) anti-proliferative signal through the downregulation of fuse-binding protein (FBP)31. A splice variant of AIMP2, AIMP2-DX2, compromises the tumour suppressive activity of AIMP2 and can induce tumorigenesis39. Among the ARSs that form the MSC, EPRS can function as a translational silencer to suppress the generation of vascular endothelial growth factor A (VEGFA), which is an angiogenic factor53. KRS can translocate to the nucleus to bind microphthalmia-associated transcription factor (MITF), which is an oncogenic transcriptional activator, and can generate the second catalytic product, diadenosine tetraphosphate (Ap4A). Ap4A binds a tumour suppressor histidine triad nucleotide binding protein 1 (HINT1), leading to the release of MITF, which is bound to HINT1 (Ref. 114). KRS is secreted and induces the production of TNF from macrophages69. QRS can interact with apoptosis signal-regulating kinase 1 (ASK1) to suppress apoptotic signals in a glutamine-dependent manner50 and MRS can increase ribosomal RNA biogenesis in the nucleoli48. Among free-form ARSs, tryptophanyl-tRNA synthetase (WRS) is secreted, and the truncation of the amino-terminal peptide generates an active cytokine that suppresses angiogenesis58. Tyrosyl-tRNA synthetase (YRS) is also secreted and cleaved into N- and C-domains that have pro-angiogenic and immune activation functions, respectively63.
Kim S, You S, Hwang D.Aminoacyl-tRNA synthetases and tumorigenesis: more than housekeeping. Nat Rev Cancer 11:708-718

September 2011


683 Reads

Over the past decade, the identification of cancer-associated factors has been a subject of primary interest not only for understanding the basic mechanisms of tumorigenesis but also for discovering the associated therapeutic targets. However, aminoacyl-tRNA synthetases (ARSs) have been overlooked, mostly because many assumed that they were simply 'housekeepers' that were involved in protein synthesis. Mammalian ARSs have evolved many additional domains that are not necessarily linked to their catalytic activities. With these domains, they interact with diverse regulatory factors. In addition, the expression of some ARSs is dynamically changed depending on various cellular types and stresses. This Analysis article addresses the potential pathophysiological implications of ARSs in tumorigenesis.

Gupta RA, Dubois RNColorectal cancer prevention and treatment by inhibition of Cox-2. Nature Rev Cancer 1: 11-21

November 2001


410 Reads

Population-based studies have established that long-term intake of non-steroidal anti-inflammatory drugs (NSAIDs), compounds that inhibit the enzymatic activity of cyclooxygenase (COX), reduces the relative risk for developing colorectal cancer. These studies led to the identification of a molecular target, COX-2, that is involved in tumour promotion during colorectal cancer progression. Recent studies in humans indicate that therapy with specific COX-2 inhibitors might be an effective approach to colorectal cancer prevention and treatment.

Ludwig JA, Weinstein JNBiomarkers in cancer staging, prognosis and treatment selection. Nat Rev Cancer 5(11): 845-856

December 2005


215 Reads

Advances in genomics, proteomics and molecular pathology have generated many candidate biomarkers with potential clinical value. Their use for cancer staging and personalization of therapy at the time of diagnosis could improve patient care. However, translation from bench to bedside outside of the research setting has proved more difficult than might have been expected. Understanding how and when biomarkers can be integrated into clinical care is crucial if we want to translate the promise into reality.

Downward JTargeting RAS signalling pathways in cancer therapy. Nat Rev Cancer 3(1): 11-22

February 2003


3,891 Reads

The RAS proteins control signalling pathways that are key regulators of several aspects of normal cell growth and malignant transformation. They are aberrant in most human tumours due to activating mutations in the RAS genes themselves or to alterations in upstream or downstream signalling components. Rational therapies that target the RAS pathways might inhibit tumour growth, survival and spread. Several of these new therapeutic agents are showing promise in the clinic and many more are being developed.

Figure 1: Protein and mRNA products of human vascular endothelial growth factor A (VEGF-A).a | Gene structure of human VEGF-A. VEGF-A spans 16,272 bp of chromosome 6p12 and consists of eight exons. Alternate 5' and 3' splice site selection in exons 6, 7 and 8 generate multiple isoforms. Exons 6 and 7 encode heparin binding domains. The transcriptional start site (TSS) and translational start site (ATG) in exon 1 are indicated. Alternative stop codons within exon 8 are also indicated (TGA1 and TGA2). b | Alternative splicing can occur either at the 5' donor splice site (for example, VEGF-A189 versus VEGF-A206) or the 3' acceptor splice site (for example, VEGF-A189 versus VEGF-A165). Two mRNA isoform families are generated. The pro-angiogenic isoforms (VEGF-Axxx, left) are generated by proximal splice site (PSS) selection in exon 8 and the anti-angiogenic family (VEGF-Axxxb, right) from exon 8 distal splice site (DSS) choice. Thus, VEGF-A165, formed by PSS selection in exon 8, has VEGF-A165b as its DSS sister isoform11, the DSS-selected mRNA encoding a protein of exactly the same length. Exon 6a' occurs in VEGF-A183 as a result of a conserved alternative splicing donor site in exon 6a and is 18 bp shorter than full-length exon 6a. VEGF-A148 is a truncated isoform splicing from exon 7a into exon 8a out of frame and resulting in a premature stop codon71. VEGF-A206b has not yet been identified. c | Protein structure of VEGF-A containing the dimerization sites and binding sites for heparin, VEGF-A receptor 1 (VEGFR1; encoded by exon 3) and VEGFR2 (encoded by exon 4), which are present in all isoforms. The six amino acids at the extreme carboxyl terminus of the protein can be either pro-angiogenic (CDKPRR, encoded by exon 8a) or anti-angiogenic (SLTRKD, encoded by exon 8b). The epitopes recognized by most commercial antibodies are in the region of the VEGF-A receptor-binding domains, present in VEGF-A isoforms of both families. UTR, untranslated region.
Figure 2: Vascular endothelial growth factor A (VEGF-A) C' terminal splicing regulation.a | The C' terminal domain of RNA polymerase II (Pol II) interacts with both transcription factors (TFs) and splicing factors (SFs). SFs are recruited to the transcriptional machinery owing to their interaction with Pol II72, 73. These SFs recognize cis-acting RNA splicing sequences in the pre-mRNA and both splicing sites (SS) — 5' donor (5'SS) or 3' acceptor sites — can be recognized. Both 3' proximal SS (3'PSS) and distal SS (3'DSS) are indicated. The particular splicing factors recruited are dependent on the sequence. These SFs can be regulated by SF kinases (SFKs), which are regulated by cell signalling molecules (CSMs) downstream of growth factors (GFs). b | Regulation of VEGF-A C' terminal PSS selection by insulin-like growth factor (IGF). IGF activates protein kinase C (PKC), which results in phosphorylation of SR protein kinases (SRPKs). These can activate the ASF–SF2 splicing factor, which favours PSS selection. This process may be dependent on the presence of hypoxia-inducible factor (HIF), a transcription factor involved in VEGF-Axxx upregulation13. Other SFs and kinases may also be involved in PSS and DSS selection, denoted by '??'. c | Factors affecting VEGF-A C' terminal DSS selection. Transforming growth factor 1 (TGF1) results in p38 mitogen-activated protein kinase activation and subsequent activation of the kinases CLK1 and CLK4. CLK1 and CLK4 phosphorylate the splicing factor SRP55, resulting in DSS selection and production of VEGF-Axxxb13. It is also possible that ASF–SF2 is inactivated by CLK1 and CLK4, or that phosphorylation of the SFs could change their location, degradation or binding affinity. This scheme summarizes the limited data available.
Figure 3: Signalling pathways downstream of vascular endothelial growth factor (VEGF-A)xxx and VEGF-Axxxb.a | The VEGF-Axxx-mediated angiogenic response acts primarily through VEGF receptor 2 (VEGFR2) to initiate multiple downstream pathways15, 16. b | VEGF-A165b results in transient, weak phosphorylation and the downstream signalling (denoted '?') from such qualitatively different phosphorylation is largely unknown (see Ref. 25 for details). Erk, extracellular signal-regulated kinase; HSP27, heat shock protein 27; NOS3, endothelial nitric oxide synthase; PI3K, phosphoinositide 3-kinase; PKC, protein kinase C; RAC, Ras-related C3 botulinum toxin substrate; PLC, phospholipase C; SHB, SH2 domain-containing adaptor protein B; SHC1, SH2 domain-containing transforming protein 1; VRAP, VEGF receptor-associated protein.
Figure 4: The structure of vascular endothelial growth factor A (VEGF-A).a | Crystal structure of amino acids 4–108 of VEGF-A, which are present in all isoforms. The crystal structure of the full-length VEGF-A protein is not known as a hinge region after amino acid 108 prevents crystallization. Modified, with permission, from Ref. 74 © 1999 Elsevier B.V. b | Amino acids 4–108 of VEGF-A are shown along with the crystal structure of the final 55 residues. Crystallization of the final 55 residues of VEGF-A165 indicates two cysteine (C)-bonded double anti-parallel sheet structures (brown arrows) separated by an helix (blue cylinder). This structure is highly mobile and rotates around the hinge, and could pass through the VEGF receptor 2 (VEGFR2) binding region but not the VEGFR1 region (yellow circles)75, 76. c | Proposed structure of amino acids 108–165 of VEGF-A165. The C' terminal six residues include a cysteine with two positively charged arginines (RR) that are proposed to interact with the VEGFR binding domain22 to activate intracellular torsional rotation of VEGFR2. The RR motif therefore acts as a molecular switch by inducing a conformational change in VEGFR2. A disulphide bond77 (shown in orange) between cysteines 146 and 160 is required for VEGF-A165 activity78 and ensures that the C terminus is maintained at close proximity to the neuropilin 1 binding domain (NPBD). d | Proposed structure of amino acids 108–165 of VEGF-A165b. The C' terminal cysteine and the positively charged RR motif present in VEGF-A165 are replaced by a serine (S) and a neutral DK motif on VEGF-A165b respectively. Although the VEGFR binding domain is present, the cysteine disulphide bond is absent. Thus, the molecular interaction with VEGFR is likely to be significantly different.
Figure 5: Vascular endothelial growth factor A (VEGF-A)165b and VEGF-A165 interaction with VEGF receptor 2 (VEGFR2).a | The VEGFR2 binding site of VEGF-A165 interacts with the VEGFR2 extracellular domain. VEGF-A165 functions as a dimer and promotes the formation of VEGFR2 dimers (only one receptor is shown here for clarity) resulting in activation of the split kinase domains (green lines) and the phosphorylation of tyrosine residues 951, 1152 and 1214 (orange) and 1054 (purple). The charged residues at the carboxy-terminal end of the VEGF-A165 molecule (omitted for clarity) are required for VEGFR activation and, in receptor tyrosine kinases, this is thought to occur through torsional rotation of the intracellular domain bringing together the split kinase domains. Tyrosine 1054 is located at the mouth of the ATP binding pocket of the tyrosine kinase and, once phosphorylated, prevents the binding pocket from closing, thus resulting in a stable open structure. This results in formation of a persistently functional kinase from the split kinase domains, resulting in sustained cis- and trans- phosphorylation of the tyrosine residues on the intracellular tail, even in the presence of phosphatases. Robust tyrosine phosphorylation also results in the activation of angiogenic signalling pathways (). b | VEGF-A165b binds the VEGFR2 binding site with equal affinity to VEGF-A165 but does not bind neuropilin 1 (NRP1). The C' terminus of VEGF-A165b is neutral and there is insufficient torsional rotation for tyrosine 1054 to be phosphorylated, although weak phosphorylation of the other tyrosines can occur. Thus, the ATP binding pocket closes and the phosphorylated tyrosines can be rapidly dephosphorylated by phosphatases and trafficked much more quickly. As a result, angiogenic signalling pathways are not activated25.
Harper SJ, Bates DOVEGF-A splicing: the key to anti-angiogenic therapeutics? Nat Rev Cancer 8(11): 880-887

November 2008


1,553 Reads

The physiology of microvessels limits the growth and development of tumours. Tumours gain nutrients and excrete waste through growth-associated microvessels. New anticancer therapies target this microvasculature by inhibiting vascular endothelial growth factor A (VEGF-A) splice isoforms that promote microvessel growth. However, certain VEGF-A splice isoforms in normal tissues inhibit growth of microvessels. Thus, it is the VEGF-A isoform balance, which is controlled by mRNA splicing, that orchestrates angiogenesis. Here, we highlight the functional differences between the pro-angiogenic and the anti-angiogenic VEGF-A isoform families and the potential to harness the synthetic capacity of cancer cells to produce factors that inhibit, rather than aid, cancer growth.

Bowtell DDThe genesis and evolution of high-grade serous ovarian cancer. Nat Rev Cancer 10(11): 803-808

October 2010


168 Reads

Germline mutation in either BRCA1 or BRCA2 is associated with an increased risk of ovarian cancer, particularly the most common invasive histotype - serous carcinoma. In addition, serous ovarian cancers have an unusually high frequency of other molecular events involving BRCA pathway dysfunction. Recent findings show a high frequency of TP53 mutation, chromosomal instability, distinct molecular subtypes and DNA copy number-driven changes in gene expression. These findings suggest a model in which homologous recombination repair deficiency initiates a cascade of molecular events that sculpt the evolution of high-grade serous ovarian cancer and dictate its response to therapy.

Schwarzenbach H, Hoon DS, Pantel KCell-free nucleic acids as biomarkers in cancer patients. Nat Rev Cancer 11:426-437
DNA, mRNA and microRNA are released and circulate in the blood of cancer patients. Changes in the levels of circulating nucleic acids have been associated with tumour burden and malignant progression. In the past decade a wealth of information indicating the potential use of circulating nucleic acids for cancer screening, prognosis and monitoring of the efficacy of anticancer therapies has emerged. In this Review, we discuss these findings with a specific focus on the clinical utility of cell-free nucleic acids as blood biomarkers.

Mehlen, P, Delloye-Bourgeois, C and Chédotal, A. Novel roles for Slits and netrins: axon guidance cues as anticancer targets? Nat Rev Cancer 11: 188-197
Over the past few years, several genes, proteins and signalling pathways that are required for embryogenesis have been shown to regulate tumour development and progression by playing a major part in overriding antitumour safeguard mechanisms. These include axon guidance cues, such as Netrins and Slits. Netrin 1 and members of the Slit family are secreted extracellular matrix proteins that bind to deleted in colorectal cancer (DCC) and UNC5 receptors, and roundabout receptors (Robos), respectively. Their expression is deregulated in a large proportion of human cancers, suggesting that they could be tumour suppressor genes or oncogenes. Moreover, recent data suggest that these ligand-receptor pairs could be promising targets for personalized anticancer therapies.

Thomas C, Gustafsson JAThe different roles of ER subtypes in cancer biology and therapy. Nat Rev Cancer 11(8): 597-608

July 2011


120 Reads

By eliciting distinct transcriptional responses, the oestrogen receptors (ERs) ERα and ERβ exert opposite effects on cellular processes that include proliferation, apoptosis and migration and that differentially influence the development and the progression of cancer. Perturbation of ER subtype-specific expression has been detected in various types of cancer, and the differences in the expression of ERs are correlated with the clinical outcome. The changes in the bioavailability of ERs in tumours, together with their specific biological functions, promote the selective restoration of their activity as one of the major therapeutic approaches for hormone-dependent cancers.

Gay LJ, Felding-Habermann BContribution of platelets to tumour metastasis. Nat Rev Cancer 11(2): 123-134

February 2011


201 Reads

Experimental evidence suggests that platelets contribute to metastasis through adhesive and haemostatic functions that promote cancer cell survival, immune evasion and interactions with vascular cells to assist organ colonization from the bloodstream. Extensive experimental evidence shows that platelets support tumour metastasis. The activation of platelets and the coagulation system have a crucial role in the progression of cancer. Within the circulatory system, platelets guard tumour cells from immune elimination and promote their arrest at the endothelium, supporting the establishment of secondary lesions. These contributions of platelets to tumour cell survival and spread suggest platelets as a new avenue for therapy.

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