6 hallmarks of cancer Flashcards
what are the 6 hallmarks of cancer?
resist cell death induce replicative immortality evade growth suppression Sustain proliferation signals inducing angiogenesis activate invasion and metastasis
what are the 4 types of cancers?
carcinomas (epithelial cells) sarcomas (connective tissue) lymphomas (lymphatic system) leukemias (white blood cells)
What are some ways cancer cells are able to ‘sustain proliferation signals’
mutations in growth signalling pathways (either increased expression of the growth signal cell receptors, increased affinity of the receptors for the growth signals, mutations in the downstream signalling molecules so that they do not need to be extracellular signals to be activated, may produce growth factor ligands themselves: autocrine proliferative stimulation, may send signals to stimulate normal cells within the supporting tumor-associated stroma, which reciprocate by supplying the cancer cells with various growth factors, disruptions of negative-feedback mechanisms that attenuate proliferative signaling, i.e. loss of PTEN (which turns PIP3 back to PIP2)
What are some ways cancer cells are able to ‘evade growth suppression’
mutations in the cell cycle checkpoint proteins (tumour suppressor proteins): Rb and P53 proteins. RB transduces growth-inhibitory signals that originate largely outside of the cell, TP53 receives inputs from stress and abnormality sensors that function within the cell’s intracellular operating systems mutations in genes that are involved in contact inhibition: NF2. NF2 gene produces merlin. Merlin adheres E-cadherin to transmembrane tyrosine kinase (EGFR). or LBK1 which induces cell membrane polarity and keeps them in an organised manner. Corruption of the TGF-b Pathway Promotes Malignancy
What are some ways cancer cells are able to ‘resist cell death’
Pathways leading to apoptosis, autophagy, and necrosis all play a role. Tumor cells evolve a variety of strategies to limit or circumvent apoptosis. Most common is the loss of TP53 tumor suppressor function, which eliminates this critical damage sensor from the apoptosis-inducing circuitry. Alternatively, tumors may achieve similar ends by increasing expression of antiapoptotic regulators (Bcl-2, Bcl-xL) or of survival signals (Igf1/2), by downregulating proapoptotic factors (Bax, Bim, Puma), or by short-circuiting the extrinsic ligand-induced death pathway Autophagy is induced in cellular starvation. It keeps cells in a quiescent state and may promote survival in poor conditions only to be reactivated when conditions return to normal. Beclin 1 binds to the BH3 domain of BLC2 and releases it from Bak and Bax –> apoptosis through release of cytochrome c which activates caspace 8. Necrosis Has Proinflammatory and Tumor-Promoting Potential. When cells die via necrosis, IL10, TGFb among other cytokines are released which recruit macrophages and fibroblasts. These clean up debris and in tumour cells may induce macropages to turn into tumour supporting cells. necrotic cells can release bio- active regulatory factors, such as IL-1a, which can directly stim- ulate neighboring viable cells to proliferate, with the potential, once again, to facilitate neoplastic progression
What are some ways cancer cells are able to ‘enable replicative immortality’
To generate macroscopic tumours cells need to have replicative immortality. This involves: telomeres, cells evading crisis phase, delayed telomerase activation, absence of TP53-mediated surveillance of genomic integrity may permit other incipient neoplasias to survive initial telomere erosion and attendant chromosomal breakage-fusion-bridge (BFB) cycles, telomerase also activates the Wnt pathway by serving as a cofactor of the b-catenin/LEF transcription factor complex + thereby sustaining cell proliferation and inhibiting apoptosis.
What are some ways cancer cells are able to ‘induce angiogenesis’
there are angiogenesis promoters: VEDGF-A and angiogenesis inhibitors: TSP-1 and plasmin fragments and type 18 collagen (endostatin) VEGF signaling via three receptor tyrosine kinases (VEGFR-1–3) is regulated at multiple levels. VEGF ligands can be sequestered in the extracel- lular matrix in latent forms that are subject to release and activa- tion by extracellular matrix-degrading protease. Hypoxia induces angiogenesis. bone marrow cells (macrophages, neutrophils, mast cells and myeloid progenitors protect the vasculature from the effects of drugs targeting endothelial cell signaling)
What are the blood vessels within tumours like? How are they different to normal vasculature?
precocious capillary sprouting, convoluted and excessive vessel branching, distorted and enlarged vessels, erratic blood flow, microhemorrhaging, leakiness, and abnormal levels of endothelial cell proliferation and apoptosis aberrant, no real structure, thrombotic.
Normal vasculature have different phenotypic expression and
What are some ways cancer cells are able to ‘activate invasion and metastasis’
best characterized alteration involved the loss by carcinoma cells of E-cadherin, a key cell-to- cell adhesion molecule, with expression of N-cadherin (an adhesion molecule that is normally expressed in migrating neurons) epithelial-mesenchymal transition (reversible)
conversion from a polygonal/epithelial to a spindly/fibro- blastic morphology, expression of matrix-degrading enzymes, increased motility, and heightened resistance to apoptosis
mesenchymal stem cells (MSCs) present in the tumor stroma have been found to secrete CCL5/RANTES in response to signals released by cancer cells; CCL5 then acts reciprocally on the cancer cells to stimulate invasive behavior
Macrophages at the tumor periphery can foster local invasion by supplying matrix-degrading enzymes such as metalloprotei- nases and cysteine cathepsin proteases
What is the invasion metastasis cascade?
local invasion
intravasation
transit in blood or lymph
extravasation
formation of small nodules (micro metastases)
colonisation
what transcriptional factors are involved in EMT?
Snail, slug, twist and Zeb1/2
A set of pleiotropically acting transcriptional factors, including Snail, Slug, Twist, and Zeb1/2, orchestrate the EMT and related migratory processes during embryogenesis; most were initially identified by developmental genetics. These transcriptional regulators are expressed in various combinations in a number of malignant tumor types and have been shown in experimental models of carcinoma formation to be causally important for programming invasion; some have been found to elicit metas- tasis when ectopically overexpressed
what type of cancer is EMT characteristic of?
carcinomas (Hint in the name: epithelial)
how to macrophages and cancer cells interact to allow for intravasation?
cancer cells release MCSF-1 that cause growth proliferation and survival of these tumor-associated macro- phages (TAMs)
TAM in turn supply epidermal growth factor (EGF) to cancer cells,
their concerted interactions facilitate intravasation into the circulatory system and metastatic dissemination of the cancer cells
is dissemination linked to colonisation?
yes but it doesnt always have to be. For example, a primary tumour can disseminate ledaing to micrometastases that never progress to macroscopic metastatic tumours.
This may be because the primary tumour releases systemic tumour suppressor factors that render them dormant as revealed clinically by explosive metastatic growth soon after resection of the primary growth- KEEPING THE CANCER IN THE PERSON IS ACTUALLY KEEPING THEM ALIVE.
In others, however, such as breast cancer and melanoma, macroscopic metastases may erupt decades after a primary tumor has been surgically removed or pharmaco- logically destroyed; these metastatic tumor growths evidently reflect dormant micrometastases that have solved, after much trial and error, the complex problem of tissue colonization
nutrient starvation can induce intense autophagy that causes cancer cells to shrink and adopt a state of reversible dormancy; such cells may exit this state and resume active growth and proliferation when changes in tissue microenviron- ment, such as access to more nutrients
micrometastatic dormancy may involve anti-growth signals embedded in normal tissue extracellular matrix
what are the 2 emerging hallmarks of cancer cells and what are the enabling characteristics that allow for these hallmarks to develop?
- evade immune destruction
- deregulating cellular energetics (i.e. metabolism alteration)
- genomic instability
- tumor promoting inflammation
whats the difference between cancer cells and cancer stem cells?
cancer stem cells divide slower and more controlled and reside within the stem cell niche of the heterogenous tumour population
there are less cancer stem cells than cancer cells
EMT may produce CSC
phenotypic plasticity between the two
CSC may underlie tumour dormancy
CSC can differentiate into their own tumour associated stroma (i.e. form endothelial cells for neovasculature) (sequencing of the genomes of cancer cells microdissected from different sectors of the same tumor (Yachida et al., 2010) has revealed striking intratumoral genetic heterogeneity)
can you label the cells part of a cancerous tumour?
Label the cell types. What is Hh? What is Hgf?
Hgf is released by cancer associated fibroblasts
It is known as hepatocyte growth factor (named so after hepatocytes self renewing regenerative capacity)- it encourages MET and phenotypic plasticity of fibroblasts –> cancer assocaited fibroblasts
The levels of MET: EMT determine whether a cancer tumour disseminates or grounds itself in the tissue, therefore MET is extremely important post dissemination and extravasation for formation of micrometastates and colonisation of the secondary site.
What is the difference between staging and grading?
Staging 1-4 (determines the invasiveness of the tumour) (TNM staging system: tumour, nodal status and metastasis)
i.e. TO (no carcinoma) TIS (carcinoma in situ) T1-T4 (size and extent of the tumour)
N0 (no nodal) (increasing N number the increasing lymph nodes)
M0 (no metastasis) (M1 number of metastasis or location)
Grading (a histological examination of the tumour looking at the cells degree of diffrentiation and dysplasia)
