L1 - Cancer history and overview Flashcards
What percentage of tumours are non-cancer cells?
35-65%
Cancer definition
Cancer cells typically follow the following trends:
- Escaped the normal limitations of external cue-driven cell division
- Have modified their local environment to exceed the naturally defined tissue borders
- Forms a multicellular mass driven by a “transformed” cancer cell
- Have mechanisms to survive immune surveillance and cell death
Examples of cell growth stimulators
- Epidermal Growth Factor (EGF)
- Fibroblast Growth Factor (FGF)
- Estrogen
- Testosterone
What examples are there of things that regulate cell growth and division?
- ECM proteins: collagen and laminin - can regulate cell growth and division by providing a mechanical and chemical signal
- pH
- Temperature
- Nutrient availability (sugars, lipids, amino acids etc)
- Cytokines - small proteins that are released primarily by immune cells and stimulate angiogenesis and cell cycle
What types of ECM modifications do cancer cells cause to occur?
- ECM degradation - using matrix metalloproteinases (MMPs)
- ECM remodelling - using the production and secretion of ECM proteins
- ECM crosslinking - modifying the ECM proteins by crosslinking, which makes the ECM stiffer and stronger
- ECM receptors - express receptors on their surface that bind to specific ECM proteins such as integrins
- Angiogenesis - promote the formation of new blood vessels
How are cancer cells transformed?
Repeated mutations through natural selection to bypass all cancer prevention and thrive
How do cancer cells ignore the immune system?
As Cd4, Cd8, Nk, Nkt (etc) cells eliminate cancer cells, further mutations are required to avoid Elimination
Once cancer has reached a point that it is in balance with the killer cells, it is in Equilibrium
Once the cancer cells have outnumbered the killer cells (may be due to growth or could be due to other illnesses weakening the immune system), the cancer cells can Escape and reign terror!
What methods of cell death are there?
Programmed cell death:
* Programmed necrosis
* Autophagy
*Apoptosis
Non-programmed cell death:
* Necrosis - mitochondrial and cell swelling, membrane rupture
Programmed cell death
- Programmed necrosis - Pyroptosis, ferroptosis, necroptosis, and parthonatos
- Autophagy - membrane, blebbing, autophagy vacuoles, and increased lysosomal activities
- Apoptosis - chromatin condensation, nuclear fragmentation, apoptotic body, membrane blebbing, cell shrinking (animal cells)
Programmed necrosis
- Pyroptosis - Maintained mitochondrial activity, cell swelling, membrane rupture
- Ferroptosis - Mitochondrial swelling, cell swelling, membrane rupture
- Necroptosis - chromatin condensation and nuclear fragmentation
- Parthonatos - increased membrane density, small mitochondria
What mechanisms are there to avoid cell death/immune surveillance and what examples of them are there?
Mutations in genes that regulate apoptosis - p53
Upregulation of anti-apoptotic proteins - BCL-2, MCL-1 ( inhibit the initiation of apoptosis)
Downregulation of pro-apoptotic proteins: BAX/BAK
Activation of survival signalling pathways - PI3K/AKT/mTOR, RAS/RAF/MEK/ERK
Altering the balance of death receptors and ligands - FAS, TNFR1
What cells does cancer come from?
- Epithelial cells
- Mesenchymal cells
- Hematopoietic cells
- Lymphoid cells
- Germ cells
- Gliomas
- Meningiomas
- Pituitary tumors
- Neuroblastomas
- Schwannomas
Epithelial cells: what are they and what cancers do they give rise to?
These cells line the surface of internal organs and glands, forming barriers
Epithelial cells can give rise to a wide variety of carcinomas, including lung carcinoma, colon carcinoma, and breast carcinoma
Mesenchymal cells: what are they and what cancers do they give rise to?
These cells form the connective tissue multiple cell types, including bone cells, muscle cells, and fat cells
They can give rise to sarcomas, such as osteosarcoma (bone cancer) and leiomyosarcoma (a cancer of smooth muscle tissue)
Hematopoietic cells: what are they and what cancers do they give rise to?
Cells found in the bone marrow that give rise to blood cells
Can give rise to leukemias, such as acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML)
Lymphoid cells: what are they and what cancers do they give rise to?
These cells are a type of white blood cell that are important for the immune system
They can give rise to lymphomas, such as Hodgkin lymphoma and non-Hodgkin lymphoma
Germ cells: what are they and what cancers do they give rise to?
These cells are responsible for producing eggs and sperm
They can give rise to germ cell tumours, such as testicular seminoma and ovarian teratoma
Glial cells: what are they and what cancers do they give rise to?
Supportive cells within the brain
Gliomas are the most common type of brain tumor and can occur in different parts of the brain - examples include astrocytomas, which arise from astrocytes (a type of glial cell), and oligodendrogliomas, which arise from oligodendrocytes (another type of glial cell)
Meningeal cells: what are they and what cancers do they give rise to?
Protective layers that surround the brain and spinal cord
Meningiomas are usually benign tumours, but in rare cases, they can be malignant
Pituitary tumours: what are they and how malignant are they usually?
Arise from the pituitary gland, a small gland located at the base of the brain
Pituitary tumours can be benign or malignant and affect hormone production in the body
Neuroblastomas: what are they caused by and where are they most common?
These tumors arise from the nerve cells in the brain or spinal cord
They are most common in infants and young children
Schwannomas: what are they caused by and what other names can they have?
These tumours arise from the Schwann cells, which are the supportive cells that surround nerve fibres
Schwannomas are also called acoustic neuromas when they arise from the cranial nerve responsible for hearing and balance
Cancer: what kinds of sub-types are there?
Histological sub-typing: microscopic appearance of the cancer cells and the structure of the tumour - for example, breast cancer ductal carcinoma (cancer that begins in the milk ducts) and lobular carcinoma (cancer that begins in the lobules of the breast)
Molecular sub-typing - This method looks at the genetic and molecular characteristics of the cancer cells. For example, melanoma mutant BRAF or mutant RAS or loss of NF1 or other
Immunohistochemical sub-typing - This method looks at the proteins expressed in cancer cells EGFR/ER/PR
Imaging sub-typing - This method looks at the imaging features of the tumour, such as size, location, and shape, and how it appears on x-ray, CT scan, MRI or PET scans
TNM system: what is it and what are the meanings of all of its numbers?
Tumour, Nodes, Metastasis system - used to determine the depth of cancer growth and spread
T (tumour) – how far the tumour has grown through the bowel wall:
- T1 – the tumour is in the inner layer of the bowel
- T2 – the tumour has grown into the muscle layer of the bowel wall
- T3 – the tumour has grown into the outer lining of the bowel wall
- T4 – the tumour has grown through the outer lining of the bowel wall
N (nodes) – whether the cancer has spread to nearby lymph nodes:
- N0 – no lymph nodes contain cancer cells
- N1 – cancer cells in up to three nearby lymph nodes
- N2 – cancer cells in four or more nearby lymph nodes
M (metastases) – whether the cancer has spread (metastasised) to other parts of the body
- M0 – the cancer hasn’t spread to other parts of the body
- M1 – the cancer has spread to other parts of the body, like the liver or lungs
IL-beta: how does it both inhibit and support cancer development?
- Suppresses it by inhibiting cancer cell proliferation
- Also supports angiogenesis
HIF: what does it do and how does it work in cancer?
Hypoxia-induced factor - released in environments of low oxygen, causes cells to be senescent
Cancer cells ignore this and grow and survive regardless
Step-wise model of cancer development?
Step 1 - mutation removes a negative regulator of the cell cycle (ie tumour suppressor)
Step 2 - mutation activates a positive regulator of the cell cycle (ie oncogene)
Step 3 - mutation inhibits cell death, potentially additives from TME
Step 4 - Fully transformed cancer cell
Cancer hallmarks
- Self-sufficiency in growth signals
- Insensitivity to anti-growth signals
- Evading cell death
- Avoiding immune destruction
- Sustained angiogenesis
- Tumour-promoting inflammation
- Limitless replicative potential
- Tissue invasion and metastasis
- Genome instability and mutation
- Deregulating cellular energetics
