EuPA Open Proteomics 8 (2015) 104–115 Contents lists available at ScienceDirect EuPA Open Proteomics journal homepage: www.elsevier.com/locate/euprot Transforming growth factor-b, MAPK and Wnt signaling interactions in colorectal cancer Harish R. Cherukua, Abidali Mohamedalib, David I. Cantora, Sock Hwee Tanc, Edouard C. Niced, Mark S. Bakera,* a Department of Biomedical Sciences, Faculty of Health and Medical Sciences, Macquarie University, New South Wales 2109, Australia b Faculty of Science, Macquarie University, New South Wales 2109, Australia c National University Heart Centre, National University of Singapore, Singapore d Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia ARTICLE INFO ABSTRACT Article history: In non-cancerous cells, transforming growth factor-b (TGFb) regulates cellular responses primarily Received 27 February 2015 through Smad signaling. However, during cancer progression (including colorectal) TGFb promotes Received in revised form 15 June 2015 tumoral growth via Smad-independent mechanisms and is involved in crosstalk with various pathways Accepted 16 June 2015 like the mitogen-activated protein kinases (MAPK) and Wnt. Crosstalk between these pathways Available online 2 July 2015 following activation by TGFb and subsequent downstream signaling activity can be referred to as a crosstalk signaling signature. This review highlights the progress in understanding TGFb signaling Keywords: crosstalk involving various MAPK pathway members (e.g., extracellular signal-regulated kinase (Erk) 1/2, Transforming growth factor-b Ras, c-Jun N-terminal kinases (JNK) and p38) and the Wnt signaling pathway. Colorectal cancer ã TGFb crosstalk 2015 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND MAPK pathways license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Wnt 1. Introduction is at initial diagnosis. Despite the availability of numerous screening strategies (Table 1) aggressive surgical therapies and extensive Globally, colorectal cancer (CRC) was the third most commonly research on the genomic, molecular and cellular basis of CRC, diagnosed cancer in 2012 with over 1.36 million new cases (9.7% of detection at the earliest stages remains elusive. all cancers). Then, it led to almost 694,000 deaths (i.e., 8.5% of all If detected early, CRC is associated with excellent 5-year cancer deaths) [1]. Australia and New Zealand have one of the survival (>90%) following simple (often curative) surgical resec- highest incidence rates globally (44.8 and 32.2 per 100,000 in men tion, while patients diagnosed with later stage cancers (ACPS or and women respectively), whilst the lowest rates are found in Dukes’ C or D) experience recurrence and distant metastases Middle Africa (4.5 and 3.5 respectively per 100,000 in men and leading to particularly poor 5-year survival rates of less than 10% women respectively) [1]. [4]. This progressive decrease in survival rates between early to late Diagnostically, various staging systems have been developed to stage CRCs (90–10%) has been shown to be associated with the describe progression of the severity of the disease (e.g., TNM disruption of a number of well-established signaling pathways Classification of Malignant Tumours, Australian Clinico-pathological (Supplementary Table 1). These include, but are not limited to, Staging (ACPS) System [2] and Dukes’ staging system [3]). These transforming growth factor-beta (TGFb)-Smad signaling, mitogen- staging tools, usually obtained from patho-histological analyses of activated protein kinase (MAPK) signaling pathways and Wnt CRC biopsies, help clinical oncologists to assess size, location and the signaling. This review will briefly discuss TGFb ligands, their spread of the cancerous lesion to other parts of the body and aid in receptors, TGFb canonical signaling through Smads and will patient treatment and management. Many studies have shown that highlight recent findings concerning its role/s in CRC and CRC survival rates primarily dependent on how advanced the cancer extensively focusing on the signaling crosstalk of TGFb with the above-mentioned pathways. TGFb, or proteins in associated pathways, could be used as early detection biomarkers that may, in the long term, improve survival and management of the * Corresponding author at: Faculty of Health and Medical Sciences, 2 Technology Place, Macquarie University, New South Wales 2109, Australia. Fax: +61 2 9850 8313. global CRC health burden. A list of potential early detection E-mail address: [email protected] (M.S. Baker). biomarkers for CRC is provided in Table 2. http://dx.doi.org/10.1016/j.euprot.2015.06.004 1876-3820/ã 2015 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/ 4.0/). H.R. Cheruku et al. / EuPA Open Proteomics 8 (2015) 104–115 105 Table 1 Currently available/emerging CRC screening strategies, ns: not specified. Test Sensitivity Specificity Frequency Year Comments Ref. (%) (%) developed Traditional assays Colonoscopy >95 95–99 Every 1969 The current gold standard, but invasive, expensive and requires bowel [5] 10 years preparation from age 50 Sigmoidoscopy 98–100 35–70 5 years 1976 Only screens the distal colon and rectum [6] Double contrast 45 90 5 years 1920s–1930s Detects only 30–50% of tumors detected by colonoscopy. Recommended only if [7] barium enema endoscopic screening options are not available. (DCBE) Computed 90 86 5 years 1994 Becoming accepted as an alternative to colonoscopy. [8] tomography (CT) colonography Guaiac fecal occult 16–38 98–99 Yearly 1967 Detects traces of blood released from bowel cancers or their precursors (polyps or [9] blood test adenomas) into the stool. Results may be affected by consumption of red meat (GFOBT) and vitamin C. All positive FOBT tests are often followed up with colonoscopy. Fecal 56–89 91–98 Yearly 1978 Specific antibodies are used against the globin component of hemoglobin. [9] immunochemical Unaffected by dietary intake, but the epitope may be destroyed by bacterial test (FIT) enzymes in the stool giving false negatives Fecal DNA 52–91 93–97 3 years 2003 Identifies genetic alterations involved in adenoma-carcinoma progression. [10] ColoSureTM test, for example, detects methylation of the vimentin gene, an epigenetic marker. Carcinoembryonic 43 90 ns 1969 Not suitable for routine detection, but useful for monitoring recurrence. [11] antigen (CEA) Emerging assays Colon capsule >80 64–95 ns 2006 A non-invasive technique in which a capsule containing a wireless camera is [12,13] endoscopy (CCE) swallowed and transmits images of the inside of the digestive tract to an extracorporeal monitor. Second generation colon capsule endoscopy has a diagnostic sensitivity of 89% or higher to identify polyps >5 mm. MicroRNA 50–90 >70 ns 2009 miR92 reported as elevated in the plasma of CRC patients compared with controls [14,15] Blood RNA 72 70 Anytime 2008 Blood-based test which measures the RNA of seven-gene biomarker panel [16] (ColonSentry) (ANXA3, CLEC4D, LMNB1, PRRG4, TNFAIP6, VNN1 and IL2RB) extracted from peripheral blood cells SEPT9 67–96 81–99 ns 2008 Blood-based test which measures the methylated SEPT9 DNA in plasma [16] 2. TGFb superfamily ligands by proteases (e.g., plasmin) [24] and/or various matrix metal- loproteinases (MMP-2 and MMP-9) [25] by cleavage of the LAP. The TGFb superfamily consists of a large family of secreted Alternatively, conformational changes in the LAP mediated by cytokines that regulate a multitude of cellular functions and integrins avb6 [26], avb8 [27], and thrombospondin-1 [28] allow disease pathogenesis. The superfamily is divided into three major the release of active TGFb1 from its associated LAP. The activation subfamilies; TGFb, activin/inhibin/nodal branches and BMP/GDF of TGFb1 by integrin avb6 is restricted to epithelial tissues as (bone morphogenetic proteins/growth differentiation factors), all avb6 is only expressed in those cells. Equally, the expression of of whom possess diverse and complementary physiological effects. TSP-1 in some epithelial tissues suggests the possibility that The TGFb subfamily members, named for their cell transforming avb6 and TSP-1 may operate in tandem to activate latent TGFb1. A activities (i.e., cell growth and differentiation) from in vitro assays recent study has shown that methylation of the TSP-1 gene results are now unequivocally known to be involved in both tumor in suppression of TGFb1 activation in CRC [29]. Integrin avb8- suppression and tumor progression (i.e., proliferation, invasion mediated activation, however, depends on the presence of and metastases). Activin and inhibins are well known positive and MT1-MMP (MMP-14) [27]. It is therefore clear that TGFb1 can negative regulators of follicle-stimulating hormone respectively be activated via a number of different mechanisms and in various [17]. Nodal along with LEFTY-1 and LEFTY-2 is required for cellular contexts. These allow it to play an important role in formation of mesoderm and axial patterning during embryonic different cellular contexts and functions. As such, it is not development [18,19]. The GDF and BMP subfamily proteins have surprising that alterations in plasmin or plasminogen binding major roles in skeletal development [20], neurogenesis [21], and [30] and alterations in expression of MMP-2 and MMP-9 [31], regulation of ovarian folliculogenesis [22]. integrin avb6 [32] and active