Hallmarks of Cancer II Flashcards
(32 cards)
Cancer: Evasion of Apoptosis
Apoptosis can be initiated either through extrinsic or intrinsic pathways, and abnormalities are found in both pathways in cancer cells, though intrinsic is most common.
General ways cancer has limitless replicative potential
1) Some cells in cancer are always stem-like, either because an actual stem cell is affected, or because a genetic lesion imparts a stem-like ability.
2) Cancer cells acquire lesions that inactivate senescence signals and reactivate telomerase, which act together to convey limitless replicative potential.
Hypoxia, Angiogenesis, and Cancer
1) A tumor needs to be vascularized in order to survive.
2) Hypoxia of the cancer triggers angiogenesis via HIF-1-alpha, which interacts with VEGF. (This means that many cancers are treated, though not cured, with VEGF inhibitors)
3) p53 regulates angiogenesis by inducing the synthesis of angiogenesis inhibitor thrombospondin-1
Angiogenesis inhibitor thrombospondin-1
Produced by p53 in an attempt to control angiogenesis of tumors.
Signaling dudes that up-regulate VEGF expression
RAS
MYC
MAPK
These all stimulate angiogenesis.
______________ has displaced squamous cell carcinoma as the most common type.
Adenocarcinoma.
1) Seen in higher percentages of non-smokers, women, and Asians.
2) Seen in higher percentages of peripheral lung cancer.
Why? Theorized that pollution plays a role. Also that cigarettes filter only large particles that typically would get stuck in the central airway, allowing the smaller ones to escape to the periphery of the lungs.
Bronchioloalveolar carcinoma (BAC)
The name for pulmonary adenocarcinoma in situ.
Recall that carcinoma in situ means that the tissue has all of the cytologic features of malignancy without visible invasion.
Atypical adenomatous hyperplasia (AAH)
The precursor to PULMONARY adenocarcinoma
The same thing as “dysplasia”
Metastases
Process:
1) An alteration in intracellular adhesion molecules (e.g. E-cadherin) allows dissociation of cancer cells from each other [LOOSENING OF CELL-CELL CONTACTS]
2) Carcinoma breaches the basement membrane either by secreting their own proteolytic enzymes or getting other cells to do so [DEGRADATION OF ECM]
3) Then, tumor cells attach to ECM proteins; when MMPs cleave collagen IV and laminin, new sites that bind to tumor cells appear and stimulate migration [ATTACHMENT TO NOVEL ECM COMPONENTS]
4) Tumors secrete cytokines like autocrine motility factors that direct migration [MIGRATION OF TUMOR CELLS]
E-cadherins
Mediate the HOMOTYPIC adhesion of epithelial cells and relay signals between cells to maintain contact inhibition and prevent abnormal growth. When a cancer cell degrades the basement membrane, it is ruining the cell-cell adhesion created by E-cadherins.
Proteases that aid in degradation of the basement membrane when a cancer cell is attempting to escape
MMPs (matrix metallo-proteinases), cathepsin D, and urokinase plasminogen activator.
These are part of normal cellular response to injury, but cancer cells can release these same proteases with malicious intent; that is, they release the proteases (and encourage other cells around them to do so as well) in order to escape into the bloodstream and metastasize.
MMP9
A gelatinase that cleaves Type IV collagen of the epithelial and vascular basement membrane and stimulates the release of VEGF from ECM-sequestered pools. Cancer uses this molecule to its advantage - it secretes it (and encourages surrounding cells to secrete it) so that it can escape into the bloodstream once the collagen and basement membrane are no longer present.
Stromal cells and metastasis
Stromal cells can produce paracrine effectors to initiate cell motility.
E.g. Hepatocyte growth factor/scatter factor binds to MET on tumor cells, helping with motility. MET is a tyrosine kinase pathway that can be up-regulated and/or used to bypass targeted drug therapy.
Tumor cell behavior in circulation, and their motivation for said behavior
Tumor cells aggregate in clumps because of their homotypic adhesions and because of their ability to bind to blood cells, particularly platelets. They can also cause formation of emboli by binding coagulation factors.
Motivation: Formation of platelet-tumor aggregates may enhance tumor cell survival and implantability.
CD44
Normally used by T-cells to bind to hyaluronate on HEVs in order to extravasate into lymphoid tissues
Used by solid tumors to enhance their spread to lymph nodes and other metastatic sties
Causes for characteristic patterns of metastases
1) Drainage pathways
2) Organ tropism
The site at which circulating tumor cells leave capillaries is related to the anatomic location and vascular drainage of the primary tumor, as well as the tropism of particular tumors for specific tissues.
Metastatic organ tropism: Its determinants
The characteristic patterns of metastasis are due to drainage pathways and organ tropism.
Organ tropism: Various organs will express varying concentrations of endothelial cell ligands for adhesion molecules. A cancer cell finds the environment (ligands) it likes best. It seems that not many cancer cells enjoy muscle or spleen tissue.
For example, CXCR4 and CCR7 chemokines are receptors heavily utilized by breast cancers, whereas other chemokines might encourage development of lung cancer
Where do prostatic carcinomas prefer to spread?
Bone
Where do small cell carcinomas prefer to spread?
Liver and adrenals
Where to neuroblastomas prefer to go?
Liver and bones
How do cancer cells turn a site into their new home?
They can secrete cytokines, growth factors, and ECM molecules on resident stromal cells, which in turn make the site habitable for the cancer cell.
How does breast cancer spread to bone?
1) Breast cancer cells secrete parathyroid hormone-related protein (PTHRP)
2) PTHRP stimulates osteoblasts to make RANK ligand (RANKL)
3) RANKL activates osteoclasts, which degrade the bone matrix and release growth factors embedded within it, like IGF and TGF-B
SNAIL and TWIST
Metastatic oncogenes that encode transcription factors whose primary function is to promote epithelial-to-mesenchymal transition (EMT). One way they achieve this is through acting as repressors that down-regulate E-cadherin expression. The changes favor the development of a pro-migratory phenotype essential for metastasis.
Basically, if a cancer cell is lucky enough to have SNAIL and TWIST, it can down-regulate E-cadherin and initiate the others processes (release of MMPs, etc) that allow it to metastasize to another site in the body.
How does a cancer cell become pro-migratory?
It down-regulates epithelial markers like E-cadherin and up-regulates mesenchymal markers like vimentin.
