Preface
1
The tumor is a lesion present in an organ or tissue, with characteristics of uncontrolled growth and aberrant structure, which cannot be explained according to the known mechanisms that underlie diseases. However, the common feature of all tumors is that their cells behave in a way that bypasses some, if not all, the control mechanisms of growth and anatomical organization of normal cells.[1]
Therefore, the tumor is essentially defined as a cell’s disease characterized by a deviation in the pathological mechanisms that govern the enhancement and the cell proliferation; when these mechanisms became insufficient a clonogenic cell proliferation occurs and thus autonomous growth that has lost the ability to control and contact inhibition.[2,3]
A first classification involves the division of malignant and benign tumors, in relation to clinical behavior. However, there are general criteria that allow you to ascribe each neoplasia to the group of benign or malignant tumor . Well- differentiated cancer cells are similar to those in the tissue of origin and are essentially benign. Further away from the original features, greater is the risk of anaplasia (ie dedifferentiation) and then malignance.
The size of the cell, the characteristics of the nucleus and other internal structures, the number of mitosis, the architecture of the tissue formed and the ability to perform normal functions are features that orient towards a greater or lesser differentiation or anaplasia.
Benign tumors generally have a cohesive structure and are surrounded by a fibrous capsule. Malignant tumors tend instead to infiltrate and erode the surrounding tissue, penetrating into the adjacent structures. They do not recognize anatomical limits and can permeate the blood and lymphatic vessels and spread in the cavities. These cells are located in other organs and tissues and cause secondary tumors (metastases). There is also a borderline tumor that has a behavior intermediate between benign and malignant, in this case metastasis are infrequent and slow.
Regarding risk factors, cancer can affect people of any age but older people have a higher probability of contracting the disease because the cellular damage and mutations accumulate with time.
Preface
2
The mutations that a cell needs to accumulate before becoming a cancer cell are:
- acquiring the capacity for autonomous replication - reduction or loss of opportunity to go undergo apoptosis - acquisition of autonomy
Besides age, there are several factors that have influence over the cancer, for example, a sedentary lifestyle, inadequate consumption of fruits and vegetables, smoking, excessive consumption of alcoholic drinks and air pollution.
Drugs used in cancer therapy act by inducing cell cycle arrest or programmed cell death (apoptosis), regardless of chemical structure or mechanism of action.
The main classes of drugs have been shown experimentally a proapoptotic effects include:
- agents that damage DNA, which can cause damage as the formation of different types of inter-or intra-crosslinks catenary.
- topoisomerase inhibitors that cause breaks in the DNA double helix around its association with proteins.
- intercalating agents
- inhibitors the formation of the mitotic spindle Inhibitors of DNA synthesis
Antimetabolites that interfere with key cellular metabolic circuses.
Moreover, in many kinds of cancer has been found an aberrant expression and / or activity of specific growth factors. These proteins therefore represent an excellent therapeutic target, successfully exploited for the development of new cancer agents, effective and safe.
Growth factors are a group of extracellular polypeptides that act as mediators of cellular proliferation and differentiation. As many as 14 families of gfs and their receptors have been identified (Table 1).[4] Their effects are mediated through endocrine, autocrine or paracrine mechanisms. When these peptides bind to their membrane bound receptors, a cascade of intracellular signaling is initiated; these signals activate nuclear gene expression within the cell. Gene
Preface
3
expression may be up-regulated as well as down-regulated by growth factors; thus their effects on cellular growth may be either stimulatory or inhibitory.
Table 1. Polypeptide Growth Factors and their Receptors.[4]
Growth factor receptor Growth factors
1. Epidermal growth factor receptor erbB2 (HER-2)
erbB3 (HER-3) erbB4 (HER-4)
EGF, TGF-α, Betacellulin, HB- EGF, Amphiregulin
None identified Neuregulin Neuregulin
2. Insuline Receptor
Insulin-like growth factor receptor 1
Insulin-like growth factor receptor 2 Insulin receptor related kinase
Insulin
Insulin-like growth factor 1/
Insulin-like growth factor 2
3. Platelet-derived growth factor receptor Colony-stimulating factor-1 receptor Steel Receptor
Flk2/Flt3
Platelet-derived growth factor Colony-simulating factor-1
4. Fibroblast growth factor receptor 1
Fibroblast growth factor receptor 2 Fibroblast growth factor receptor 3
Fibroblast growth factor receptor 4
Acidic fibroblast growth factor Basic fibroblast growth factor Int-2
Hst/KFGF FGF-5 FGF-6 KGF 5. Nerve growth factor receptor
BDNF receptor NT-3 Receptor
Nerve growth factor BDNF
6. Vascular endothelial growth factor receptor 1 Vascular endothelial growth factor receptor 2
VEGF
7. Hepatocyte growth factor receptor HGF
8. Eph, Eck, Eek,
Cek4, Cek5, Cek6, Cek7, Cek8, Cek9, HEK11 9. Ror1, Ror2
10. Ret 11. Ax1
12. RYK
13. DDR
14. Tie
Preface
4
Growth factor receptors (GFR) consist of an extracellular ligand-binding domain and an intracellular tyrosine-kinase domain (TKD). When GF binds to its extracellular domain, the receptor dimarises with adjacent receptor. The two receptors are now juxtaposed so that their intracellular TKDs may phosporylate each other.[5] As TKDs are phosporylated, they become primed to bind to trasduction molecules and initiate intracellular signalling.
