# Gastrointestinall Tumors: Phytochemical and Drug Combinations Targeting the Hallmarks of Cancer
## 1 Introduction  
Carcinogenesis is the process that characterizes the transformation of normal cells into tumor cells [1]. This process is driven by the accumulation of genetic mutations and the alteration of epigenetic regulatory mechanisms [1]. During metastasis development, the spreading of primary tumor cells to distant tissues and organs takes place [2]; the metastasis cascade consists of five steps: invasion; intravasation; systemic transportation; extravasation and colonization of the new site [3]. Metastasis formation is linked to the Epithelial to Mesenchymal Transition (EMT) process [4]. In the EMT multiple, distinct cellular subpopulations are involved, including the cancer stem cells (CSCs), that can regenerate the cells of the tumor core [5]. It has been demonstrated that the cells of the core of tumor mass live in hypoxic conditions, resulting in activation of hypoxia inducible factors (HIF-1a and HIF-2\(\alpha\)), that are able to increase the expression of several genes, such as vascular endothelial growth factor A (_VEGFA_), leading to events of neo-angiogenesis and enhancement of vessel permeability [6]. In particular, HIF-1\(\alpha\) is an essential protein for EMT activation and metastasis development [7]. Importantly, there are two kinds of antitumor drugs used against tumors characterized by metastasis development: anti-angiogenic and anti-metastatic synthetic molecules; these drugs target specific characteristics of tumor cells, called hallmarks of cancer [8]. The hallmarks of cancer include: increased signaling for proliferation, evading growth inhibitors, evading apoptosis, replicative immortality, increased angiogenesis, activated invasion and metastasis development, genome mutations,pro-inflammatory conditions, altered energy metabolism and evading immune destruction, to which the tumor micro-environment contributes [1]. Furthermore, another hallmark plays a pivotal role in cancer development: the multidrug resistance (MDR) of cancer cells, acquired through overexpression of MDR genes and increased levels of P-glycoprotein (P-gp), which is involved in the efflux of chemotherapeutic drugs from tumor cells [9]. Conventional anticancer drugs specifically target over-proliferating tumor cells; importantly, new therapeutic strategies have been developed, focused on a combination of chemotherapeutic agents and chemopre [10]. The role of diet in tumor chemopre has been indicated by many authors, who described the relationship between phytochemicals present in food and their antitumor properties [11; 12; 13]. Apoptosis is the main mechanism through which phytochemicals induce the death of tumor cells, after the activation of specific enzymes called caspases [14]. Three apoptotic pathways have been described: the extrinsic pathway, where caspase 8, caspase 3 and the multi-protein complex Fas-associated protein with death domain (FADD)osome (Figure 1) play a pivotal role [1], endoplasmic reticulum pathway [15] and the intrinsic pathway [1], where caspases 2, 9 and 3 are involved [16; 17]. As regards caspase 2, this enzyme is activated by reactive oxygen species (ROS). The role of ROS, increased DNA damage and multi-protein complex p53-induced death domain containing protein (PID)osome (Figure 1) in the maturation and activation of caspase 2 has been described [16]. Noteworthy, inhibitor of apoptosis proteins (IAPs) are able to suppress the intrinsic pathway of apoptosis, in particular through an increase of Baculoviral inhibitor of apoptosis repeat-containing 5 (_BIRC_5) expression levels and survivin protein levels [18]. This IAP can inhibit the caspase 9 activity, blocking the formation of the apoptosome (Figure 1) [18]. Several phytochemicals and synthetic molecules derived from natural compounds can activate the intrinsic or the extrinsic apoptotic pathways [19; 20; 21; 22].