1. Hallmarks of cancer

What is cancer

• Not one disease

• a multistep process

• starts with one cell

• Multiple cell types involved

• Cancer cells are less responsive to regulatory circuits of cellular proliferation and cell death

The three types of hallmarks

• Core hallmarks

• Enabling characteristics

• Emerging hallmarks

Core hallmarks

Fundamental characteristics of cancer cells (these hallmarks make the cell a cancer cell)

Enabling characteristics

Conditions that facilitate the hallmarks, not specific to cancer cells

Emerging hallmarks

Newer cancer-associated characteristics for which the exact role in cancer development needs to be confirmed.

What are the six core hallmarks (2011)

• Sustaining proliferative signaling (growth and survival)

• Evading growth suppressors (growth and survival)

• Enabling replicative immortality (growth and survival)

• Activating invasion & metastasis

• Inducing angiogenesis

• Resisting cell death (growth and survival)

Cell cycle

• Proliferation

• Differentiation—specialization of the cell

• Replication

Halmark: Sustaining proliferative signaling

• More cells are caused by growth factors

• More cells are created during cancer by producing more growth factors.

  • Increase in synthesis of growth factors by tumor cells

  • Increase in synthesis of growth factors by neighboring cells

  • Increase in receptors at cell surface (that can catch the growth factors)

  • Structural alterations of the receptors increases the response

  • Activation downstream pathways

Example of sustaining proliferative signaling

• EGF: Epidermal growth factor

Hallmark: Evading growth suppressors

• As if there is no break

• Proliferation suppressors = tumor suppressor genes

• Example: Retinoblastoma-associated (RB) protein

Hallmark: resisting cell death

• Apoptosis: cell is turned into very small bodies and dies.

• Autophagy: Cell organs are engulfed and creates autophagosome

• Necrosis: Membrane is broken down.

All are resisted but there is more necrosis.

Hallmark: Enabling replicative immortality

• Normal cells: divide and therefore their telomeres become shorter

  • In cancer cells this does not happen, and therefore they have unlimited replication

  • This is because the telomeres extend

  • Cancer cells have high telomerase

Angiogenesis

• The formation of new blood vessels

• Therefore, this is important for the spreading of cancer

  • This is because cancer cells need oxygen.

  • By removing blood vessels around the tumor, the tumor can be shrunken.

• Early stage event

Inducing angiogenesis

• Hypoxia-induced expression of VEGF by tumor cells

• Stimulation of angiogensis by VEGF

• Rapid tumor growth and metastasis

Metastasis

Invasion metastasis

Key words:

• Intravasation: Moving into the blood stream

• Extravasation:

• Macro-metastasis: Creation of a new tumor

Epithelial-to-mesenchymal transition

Tumor suppressor vs. oncogene

is p53 oncogene or tumor suppressor?

Tumor suppressor gene - cell cycle arrest + apoptosis

is EGFR oncogene or tumor suppressor?

Oncogene - because it is in favor of growth (Growth factor)

Is RB oncogene or tumor suppressor?

Tumor suppressor gene - cell cycle arrest

Driver vs passenger mutation

• Passenger mutation:

  • Passenger mutation has no effect on neoplastic process

  • Number of passenger mutations correlates with age (during normal growth)

  • Predominantly in self-renewing tissues

• Driver mutation:

  • Driver gene mutation = a mutation conferring a selective growth advantage for the cell

  • Impacts ratio cell birth : cell death

Tumor - promoting inflammation

• Infiltration of immune cells

• Supplying bioactive molecules to microenvironment

• Tumor inhibition as well as tumor promotion

Emerging characterstics (2011)

• Deregulating celular energetics

• avoiding immune destruction

New emerging characteristics

• Unlocking phenotypic plasticity

• Senescent cells (about affecting the immortality of neighboring cells)

• Epigentics

• Polymorphic microbes = ‘different faces’

Markers for proliferation

Ki67 protein

• Marker (protein) for cell proliferation

• Expressed during active phases cell cycle

• Detection by immunohistochemistry

• Prognostic marker in some routine clinical work