*3.1. Cancer Hallmarks*

Tumorigenesis in humans is a multi-step process, reflecting genetic alterations that progressively lead to a continuous transformation of normal cells into highly malignant cells. Tumour genomes are altered at multiple sites, either by point mutations or by more obvious alterations, such as changes in chromosomal complement. Observations in human cancers and animal models indicate that tumour development is driven by a succession of genetic changes, which confer one or another type of growth advantage, resulting in a progressive conversion of normal cells to cancer cells. Cancer cells have defects in the signalling pathways that regulate normal cell proliferation and homeostasis. However, the cancer cells of different tumours have very broad genotype diversity. Based on this complexity, Hanahan and Weinberg proposed that these genotypes were the result of six main essential alterations: self-sufficiency in growth signals, insensitivity to growth-inhibiting signals, avoidance of programmed cell death (apoptosis), unlimited replicative potential, sustained angiogenesis, and tissue invasion and metastasis. Each of these physiological changes are capabilities acquired during tumour development that escape a cancer defence mechanism connected to cells and tissues. These six abilities are shared by most types of human tumours. These capabilities are called the "hallmarks of cancer" [74].

Later, in 2011, they determined that tumours are not just island masses of proliferating cancer cells, but are complex tissues composed of different cellular types that interact with each other. Normal cells recruited to the site of the tumour form the tumour-associated stroma and are actively involved in tumorigenesis. The biology of tumours cannot be understood by just listing the features of the cancer cells; the involvement of the tumour microenvironment must be taken into account. Four other features shared by tumours have been described: genomic instability and mutation, cellular energy dysregulation, escape from immune destruction, and tumour-promoted inflammation (Figure 4) [75]; which are also very relevant to understand the pathology to decipher therapeutically targets and also as a source for diagnostic and prognostic biomarkers.

**Figure 4.** Scheme about the described hallmarks of cancer.

The development of targeted therapies to treat cancer is currently very important and is based on research into the mechanisms of cancer pathogenesis. Different targeted therapies can be classified according to their effects on one or more cancer hallmarks and the efficacy of these drugs is a validation of each hallmark described.
