Tumor

PI3K/Akt/mTOR pathway is important for anti-apoptosis, cellular proliferation, and angiogenesis. Mutations in growth factor receptors, Akt, mTOR, or PTEN that enhance the activity of this pathway contribute to cancer pathogenesis.

Programmed death receptor (PD-1) is expressed on the surface of activated T cells. It binds to its ligand, PD-L1 --> downregulate the immune response against tumor cells primarily by inhibiting cytotoxic T cells (similar to cytotoxic T lymphocyte-associated protein 4 [CTLA-4] which binds to B7)

Note:

CD28, a T-cell specific surface protein also interacts with B7 on APCs as a costimulatory signal for T cell activation, whereas interaction between CTLA-4 and B7 triggers inhibitory function.

Many types of cancer cells evade the immune system by increasing expression of PD-L1.

Monoclonal antibodies against PD-1 have been developed that prevent the binding of PD-1 to PD-L1; this blocks T cell inhibition, thereby restoring the cytotoxic response and promoting apotosis of tumor cells.

Anti-PD-1 therapy => used in advanced melanoma and certains types of lung cancer.

Most chemical carcinogens enter the body in an inactive state (ie, as pro-carcinogens). These pro-carcinogens are converted into

active metabolites by the cytochrome P450 oxidase system (microsomal monooxygenases) in the liver. Individual susceptibility

to chemical carcinogens depends on the activity of these P450 enzymes, which is genetically determined.

Tumor Spread and Progression

1. Detachment of tumor cells from surrounding cells occurs due to decreased expression of CAMs; most tumors show down-regulation of E-cadherins
2. Detached tumor cells have the ability to adhere to basement membranes - there is increased expression of laminin and other adhesion molecules
3. Invasion of the basement membrane by using proteolytic enzymes such as metalloproteinases and cathepsin D protease