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Cancer cells have the ability to change the surrounding environment in a way assist them to grow and proliferate, they respond to any internal or external circumstances by increasing or decreasing the expression of proteins which can adjust the situations in favour of increasing the proliferative, invasive and metastasise properties of cancerous cells (Hanahan and Weinberg, 2000). The reciprocal communications between the external or internal circumstances and protein expression level take place via activation of a cascade of intracellular biochemical reactions which also called signal transduction pathways (Lobbezoo et al., 2003). Each pathway starts with ligation of extracellular receptors. The receptor activation is translated into biological response by activation of proteins (transcriptional factors) which then translocate into the nucleus and bind with the DNA in specific binding sites (promoters) and trigger the transcription of mRNA which later translated to proteins (Eccleston and Dhand, 2006).
Oncogenic gene mutations results in a constitutive activation of signal transduction elements, simulating a condition of permanent activation of the receptor, even in the absence of the relevant growth factor (Hanahan and Folkman, 1996). Wnt, Notch, TGF-Î², Myc/Max, Hypoxia, MAPK pathways were reported to be hyper-activated in cancerous cells (Clevers, 2004, Miyazawa et al., 2002, Fang and Richardson, 2005, Soucek et al., 2008, van Es and Clevers, 2005b).
On the other hand, mutations in tumor suppressor genes lead to deactivate some pathways which serve as checkpoints of cells proliferation such as p53 (Feng et al., 2008). These pathways can be targeted with signal transduction modulators (STMs) in order to treat cancer. The STMs can modulate the pathway activation at many levels such as blocking cell surface receptors, blocking the mediators between extracellular signals and the transcriptional factor, deactivate the binding between the transcriptional factors with the promoters or inhibiting the effects of further downstream genes (Lobbezoo et al., 2003).
STMs have attracted attention of many researchers. Many STMs compounds are being investigated in preclinical studies or in clinical trials. Additionally, there are two approved STMs drugs which have been commercially marketed; trastuzumab and imatinib (Lobbezoo et al., 2003).
1.4.1 (a) Wnt /Î²-catenin Signalling Pathway:
Wnt signalling pathway plays a crucial role in development process as well as cancer via controlling gene expression, cell behaviour, cell polarity and cell adhesion (Cadigan and Nusse, 1997). Wnt signals work through three pathways; Wnt /Î²-catenin pathway (referred to as canonical Wnt pathway) and the non-canonical Wnt/Ca+2 and Wnt/JNK pathways (Moon et al., 2002).
The mutations of many components of Wnt /Î²-catenin pathway were detected in many types of human cancers such as: colon cancer, melanoma, prostate and breast cancer (Morin et al., 1997, Verras and Sun, 2006, Lin et al., 2000, Chien et al., 2009). Moreover, it was found that 80% of sporadic colon cancer patients have mutation in a tumor suppressor gene called APC, which function was identified as a down-regulator of Wnt pathway (Calvert and Frucht, 2002). It is widely accepted now that mutations either in APC or Wnt /Î²-catenin pathway are the earliest events in colon oncogenesis (Kinzler and Vogelstein, 1996).
The Wnt /Î²-catenin pathway controls the expression of very essential oncogenes such as: c-Myc, cyclin D1 and matrix metalloproteinase genes which are very vital in carcinogenesis as well as angiogenesis process (Dihlmann and Magnus, 2005). Down-regulation of Wnt pathway in aim of decreasing these genes expression could regress the tumor proliferation as verified in one study which targeted expression of cyclin D1 (Tetsu and McCormick, 1999).
1.4.1 (b) Notch Signalling Pathway:
Notch cell signalling pathway is involved in a variety of cellular functions: cell fateÂ specification, differentiation, proliferation, apoptosis, adhesion,Â migration, and angiogenesis (Bolos et al., 2007). The signalling starts with the ligation of the extracellular four isoforms of Notch receptors (Kojika and Griffin, 2001).
In 1990s, the relation between Notch pathway and cancer has been identified by discovering that 10% of T-cell lymphoblastic leukemia patients have constitutive activation of Notch 1 receptor, further in vivo and in vitro studies supported the idea that activation of any of Notch isoforms is well-correlated with tumor growth and aggressiveness properties (Callahan and Raafat, 2001). Hyper-activation of notch pathway signalling has been noticed in many types of cancer, including pancreas, colon, renal, breast, lung and melanoma cancers (Wang et al., 2006, Farnie and Clarke, 2007, Sun et al., 2009, Radtke and Clevers, 2005, Strizzi et al., 2009, Collins et al., 2004).
Many studies reported the strong relation between Notch and Wnt pathways in colon cancer (van Es and Clevers, 2005a, De Strooper and Annaert, 2001, Fre et al., 2009). In mutant APC mice (the tumour suppressor gene of Wnt pathway), it was found that Wnt pathway signalling as well as Notch pathway were hyper-activated, the results strengthen the hypothesis that Notch signalling might be in a downstream of Wnt pathway. Moreover, the two pathways may work synergistically, hence both Notch and Wnt inhibitors may be combined in aim of colon cancer remedy (van Es and Clevers, 2005a). Several approaches to block notch pathway are now under investigations, among them: antisense, RNA interference and monoclonal antibodiesÂ (Nickoloff et al., 2003).
1.4.1 (c) p53 Signalling Pathway:
The p53 gene mutation is very common on all cancers; p53 is suppressed in more than 50% of all human cancer cases. p53 mutations causing activation of other oncogenic pathways, making tumor more aggressive and resistant to chemotherapy as well as radiation (Kumar et al., 2004). The relation of p53 and cancer was presented in 1980s and p53 has been called as a "Guardian of the Genome'' referred to its ability in induction of apoptosis and cell cycle arrest. p53 protein encodings many type of genes which involved in cell cycle, apoptosis and angiogenesis. p53 controls cell death by regulating the two apoptotic pathways genes; the death receptor Fas and DR-5 genes which involved in extrinsic pathway as well as Bax, Bak and Bid proteins which involved in the mitochondrial pathway (Frank et al., 2004). The impact of the p53 in apoptosis process was demonstrated in a study showed that the apoptosis process has become slower in p53 knockout-mice and as a result the tumor became more resistance (Lowe et al., 1993) .
Rescuing the p53 protein and correction its defects has attracted the attention of scientist in aim to treat cancer. Different approaches have been used and showed a remarkable activity in regression of cervical head and neck, lung, ovarian and prostate cancers (Clayman et al., 1995).
1.4.1 (d) TGF-Î² Signalling Pathway:
TGF-Î² signalling pathway is described as a double-edged sword, the tumor suppressor and oncogenic properties of this pathway were reported in many studies (Akhurst and Derynck, 2001, Sánchez-Capelo, 2005, Akhurst, 2002). In term of tumor suppression properties of TGF-Î², studies show that TGF-Î² defect- mice were more susceptible to tumor incidence than normal mice (Tang et al., 1998). Besides, transgenic mice in which the TGF-Î² is hyper-activated were found to be more resistant for mammary tumor formationÂ (Pierce et al., 1995).
On the other hand, it was confirmed that tumor cells secret TGF-Î² proteins in vitro more than normal cells (Roberts et al., 1983). TGF-Î² plasma concentrations as well as TGF-Î² urinary excretion rate of cancer patients were higher than normal values (Nishimura et al., 1986, Tsushima et al., 1996). Additionally, a strong correlation between TGF-Î² concentrations and tumor metastasis, invasive and angiogenesis has been confirmed (Bierie and Moses, 2006). All these studies indicate that TGF-Î² has a negative impact on tumor prognosis (Tsushima et al., 1996). Many studies conclude that the over expression of TGF-Î² pathway can work as a tumor suppressor gene at the early stages of cancer, however, after that this pathway serve as an oncogenic pathway and supports angiogenesis, metastasis and invasive properties of tumor cells (Bierie and Moses, 2006, Massagué, 2008). Nevertheless, the obvious mechanistic explanation of the dual effects is still ambiguous.
Targeting this pathway has shown a promising results in cancer treatment, different approaches have been used such as: antisense and ligand-receptor binding inhibition by using antibodies targeting the TGF-Î² or the receptors (Massagué, 2008). However, the pharmaceutical companies still fear to produce any target of this pathway because the non-selectivity and the side effects which may arise from the dual activity (Akhurst, 2002).
1.4.1 (e) Cell Cycle (pRB/ E2F) Signalling Pathway:
The retinoblastoma tumor suppressor (pRB) is an essential contributor in apoptosis and cell cycle processes. The pRB gene which encodes pRB proteins has been found to be mutated in approximately 50% of all human tumors. Additionally, genes encoding upstream regulators of pRB have been reported mutated in the remaining 50% of all human tumors. These facts strongly propose the tumor suppressor properties of pRB pathway (Frank and Yamasaki, 2004).
Investigated studies on retinoblastoma cases showed that more than 40 % of cases are inherited; further studies explained this by inactivation of tumour suppressor gene which is called later as pRB tumor suppressor gene (Draper et al., 1992). Using DNA cloning techniques, the influence of pRB protein was confirmed in many type of cancers such as: bladder, breast, lung, leukemia and prostate (Weinberg, 1991). In-vitro experiments which involved introducing pRB protein in cancer cells came to an end with inhibition of cell proliferation at stage S of the cell cycle (Bandara and La Thangue, 1991). The function of pRB is supported by using pRB knockout mice, which developed many types of neuro-cancers such as: pituitary adenocarcinomas, pheochromacytomas and thyroid C-cell adenomas (Harrison et al., 1995, Nikitin et al., 1999).
The pRB signalling pathway is activated by binding the pRB protein with many transcriptional factors, among them, E2F seems to be the most important (Bandara and La Thangue, 1991). The active dimer then binds with its promoters which control the expression of many vital genes in cell death process such as genes of the regulators of c-Myc, thymidylate synthase, N-Myc, cdc2, thymidine kinase, cyclin A, dihydrofolate reductase and DNA polymerase (Helin and Ed, 1993).
1.4.1 (f) NF-ÐºB Signalling Pathway:
NF-ÎºB Suppresses cell death and supports cell growth, metastasis and angiogenesis. More than 200 target NF-ÐºB have been identified, among them; Myc, Rel, and Cyclin D1-4 which involved in cell cycle regulation, Bcl-2, Bcl-Xl, A1/Bf-1 which function in apoptosis process, VEGF gene which is essential in angiogenesis process, and urokinase plasminogen activator which responsible about cell metastasis (Pahl, 1999). Many experiments presented that NF-ÐºB works as a safe guard of tumor cells by protect it from apoptosis which induced by many tested synthetic and natural agents (Barkett and Gilmore, 1999). NF-ÐºB Knocked-out mice experiments proof the oncogenic roles of this pathway, as the mice died due to massive liver apoptosis at mid-gestation stage (Beg et al., 1995). In other studies, activation of this pathwayÂ has inhibited tumor regression and cell apoptosis (Li et al., 1999, Chaisson et al., 2002, Schmidt-Supprian et al., 2000).
The oncogonic activity of NF-ÐºB inspired researchers to discover or synthesis compounds target this pathway, for instance cinnamaldehyde which was reported as an apoptosis inducer compound via mitochondrial pathway, was reported recently as a potent NF-ÐºB pathway inhibitor (Ka et al., 2003, Reddy et al., 2004).
1.4.1 (g) MYC/MAX Signalling Pathway:
MYC/MAX pathway have been found to be hyper-activated in 70% of all human cancer cases which strongly suggesting the oncogenesis properties of this pathway (Nilsson and Cleveland, 2003). The MYC/MAX pathway was also found essential in cell cycle process, in absence of this protein the cell cycle can't beyond the S phase (Heikkila et al., 1987). Besides its role in cell proliferation, MYC/MAX plays a role in triggering the angiogenic switch in favour of angiogenesis initiation (Pelengaris et al., 1999). Dimerization with Max and then binding to DNA are necessary to exhibit all MYC biological effects (Evan et al., 1992).
A significant tumor regression in transgenic mice was attained by knocking-down the MYC/MAX which paving the way to a more directed efforts in aim of targeting this pathway (Pelengaris and Khan, 2003).
1.4.1 (h) MAPK Signalling Pathways:
There are three sub-families of MAPK proteins: extracellular signal regulated enzyme kinases (MAPK/ERK), p38 MAPKs and the c-Jun amino terminal kinase (JNKs). While the main function of MAPK/JNKs and MAPK/ERKs is involved in cell cycle, regulation of mitosis, migration and apoptosis, the MAPK/p38 function is involved in inflammation (Johnson and Lapadat, 2002).
The activation of these pathways is attained by ligation the extracellular receptors, the well-studied receptor Ras is one member of this pathway. Upon activation, the MAPK signalling required activation of three MAPK chains; as MAPKKK activates a MAPKK which activates a MAPK (Makin and Dive, 2001).
Upon treatment with MAPK signalling inhibitors, the cell cycle was arrested and proliferation was inhibited in many cell lines such as: smooth muscle, epithelial, T lymphocytes, fibroblasts and hepatocytes cell lines (Meloche and Pouyssegur, 2007) .
The mechanisms by which these pathways exhibited their functions were studied thoroughly. The ability of MAPKs to regulate the cell growth was explained by it is ability to control of global protein syntheses via activation of the translation the initiation factor eIF4E as well as by direct regulation of ribosomal gene transcription (Stefanovsky et al., 2001, Morley and McKendrick, 1997). Moreover, the production of pyrimidine which is necessary to DNA and RNA synthesis is under the control of this pathway (Evans and Guy, 2004). Furthermore, the presence of this pathway is obligatory for G1- to S-phase progression. MAPKs also serve in stabilization of c-MYC protein (Sears et al., 2000). Additionally, MAPKs down regulate more than 170 tumor suppressor genes such as:Â Tob1,Â JunD and Ddit3 which inhibits cell growth and proliferation (Yamamoto et al., 2006).
Based on the crucial oncogenic activities, huge efforts were attempted in order to produce inhibitors of the ERK and JNK pathways, some of the them are in Â clinical trials stage (Kohno and Pouyssegur, 2006).
Hypoxia is defined as a decrease in the oxygen supply to a level insufficient to maintain cellular function. The cells turn into hypoxic if it is far from blood vessels. As a result of cells proliferation and tumor growth, the cells in the core of tumor get hypoxic (Carmeliet, 2005). Hypoxic cells are more invasive and metastatic, and more resistant to killing by chemotherapy or radiation (Melillo, 2007).
Recent evidence demonstrated the impact of activation of hypoxia inducible transcription factors (HIFs) in hypoxic cells in angiogenesis process (Zhong et al., 1999). Binding the HIFs with the DNA induces expression of several angiogenic factors including VEGF, nitric oxide synthase, platelet-derived growth factor (PDGF), and others (Ahmed and Bicknell, 2009, Carmeliet, 2005). The critical step in induction of this pathway is the stabilization of the HIFs. The most important two members of HIFs are HIF-1 and HIF-2. HIF-1 is ubiquitously expressed, while, HIF-2 is expressed only in endothelial cells and in the kidney, heart, lungs and small intestine (Wang et al., 1995, Semenza, 2001). HIF-1 complex is a heterodimer consisting of two DNA binding proteins, HIF-1Î± and HIF-1Î². The expression of HIF-1Î± is tightly regulated by oxygen, while the HIF-1Î² is expressed constitutively (Bracken et al., 2003, Wang et al., 1995). Under normoxic conditions, HIF-1Î± is rapidly degraded due to enzymatic prolyl-hydroxylation. However, under hypoxic conditions the stability and half life of HIF-1Î± increased remarkably. Accordingly, HIF-1Î± dimerizes with HIF-1Î². The heterodimer is then translocated to the nucleus and activates the promoter region of target genes (Wang et al., 1995). As the expression of the chief factor in the angiogenesis, VEGF, and many angiogenic pathways related directly with the activation of HIF-1, the search for drugs targeting HIF is currently receiving a lot of attention (Semenza, 2003). The notion of targeting HIFs to treat cancer was proven experimentally by a study that showed that tumor growth was reduced significantly in mice implanted with cells infected with a polypeptide which disrupted the binding of HIF-1Î± to its transcriptional co-activators (Kung et al., 2000). Several approaches targeting tumor hypoxia have been proposed, including prodrugs activated by hypoxia, hypoxia-selective gene therapy and the use of recombinant obligate anaerobic bacteria (Brown and Wilson, 2004). Besides, the mechanism of action for some antiangiogenic natural compounds such as betulinic acid, Klugine, isocephaeline, emetine and Taxol has been confirmed to involve inhibition of hypoxia pathway (Karna et al., 2010, Fan et al., 2006, Zhou et al., 2005).