W11L3 Flashcards
10 hallmarks of cancer
- Sustaining proliferative signalling
- Deregulating cellular metabolism
- Resisting cell death
- Genome instability and mutation
- Inducing or accessing vasculature
- Activating invasion and metastasis
- Tumor-promoting inflammation
- Enabling replicative immortality
- Avoiding immune destruction
- Evading growth suppressors
Several of these hallmarks are targeting cells that are not part of the tumour, such as “avoiding immune destruction”
- this suggests that there is something other than the tumor cells that are being targetted by signalling pathways
Tumour also consists of supportive cells such as cancer associated fibroblasts (are supportive of the tumor cells), tumour- associated macrophages (are anti-inflammatory so they work against the immune system), and endothelial cells in the vascular (so the tumor has nutrients), such as “tumor-promoting inflammation” and “inducing or accessing vasculature”
- “tumor-promoting inflammation” and “inducing or accessing vasculature” are not tumor specific but are required for cancer progression
Knockdown of Smad4
Knockdown of Smad4 affects only a subset of TGF-β-regulated target genes and functions.
SMAD4 was first identified as DPC4 = Deleted in Pancreatic Cancer 4
Some events downstream of TGFβ are SMAD4 independent (possibly due to non-canonical pathways)
When SMAD4 is knocked down, it inactivates growth arrest and migration. But transcription factor programs and EMT (actin reorganization, loss of adherens junction, mesenchymal phenotype) is still active even after SMAD4 knockdown
Signaling modules and genetic programs underlying EMTs induced by TGF-β.
Key events in cancer progression and metastasis, which also lead to epithelial-mesenchymal transition:
- desmosome disassembly
- adherens junctions disassembly, leading to cell motility
- cell-matrix remodelling, leading to cell motility
- F-actin remodelling, leading to cell motility
- transitional progenitor cell
Signaling modules and genetic programs underlying EMTs induced by TGF-β.
TGFβ can stimulate events via SMADs and non SMADs
Key events in cancer progression and metastasis, which also lead to epithelial-mesenchymal transition:
- desmosome disassembly
- adherens junctions disassembly, leading to cell motility
- cell-matrix remodelling, leading to cell motility
- F-actin remodelling, leading to cell motility
- transitional progenitor cell
But canonical TGFβ can also promote cancer progression through SMAD/canonical signaling
Pathways that promote cancer: tumour-promoting effects of TGFβ
- promotes cell proliferation
- suppresses the immune response
- promotes angiogenesis
- promotes cancer stem cell self-renewal
- promotes the epithelial-to-mesenchymal transition
- promotes metastasis
Pathways that suppress cancer: tumour-suppressing effects of TGFβ
- inhibits cell proliferation
- induces apoptosis
- activates autophagy
- inhibits growth factors in the tumor stroma
- inhibits angiogenesis
- suppresses inflammation
TGFβ has a dichotomous role in…
TGFβ has a dichotomous role in tumor progression
Structure of the nucleus
Heterochromatin (dark)
- Areas of gene silencing
- most genes are inactive here
Euchromatin (light)
- Areas of gene expression
- genes are active here, easily accessible for transcription factors
Nucleolus
- in the middle, dark
- region for ribosome synthesis
- Involved in cell response to stress
- Assembly of signal recognition particles
Nuclear envelope
- Made up of two phospholipid bilayers (outer and inner)
- The outer is continuous with the endoplasmic reticulum
- Structural support on inner surface by the nuclear lamina
Nuclear Lamin
Protein meshwork
Mostly made up of lamins and lamin associated proteins
– Connect to the inner nuclear membrane
– Connect to chromatin
LAP – lamin-associated protein
HP1 – heterochromatin protein 1
NPC – nuclear pore complex
Lamins
Lamin is a Type of intermediate filament found in the nucleus
- A-type – all types encoded from alternate splicing of the LMNA gene
- B-type – encoded by two genes, LMNB1 & LMNB2
- there are 2 types of Lamin B: Lamin B1 and Lamin B2
Lamin function
A-type lamins higher expression in mechanical type tissues –> skeletal and cardiac muscle
- expressed in cells that need rigid nuclei
- for structural integrity
B-type function may be disposable but more highly expressed in undifferentiated cells (embryonic stem cells)
- in cells that can move around, cells that need to migrate
- allows for flexible movement
Lamins provide:
* Structural support and shape to the nucleus
* Associate with chromosomes
* Mechanotransduction
* Regulates gene expression
Lamins are connected to LINC proteins (links between nucleus and cytoplasm)
LINCs
- Linker of nucleoskeleton and cytoskeleton
- Affects signaling pathways and gene regulation
- interacts with lamins
Integrin is attached at PM and is attached to the stroma too.
- integrin can signal down a network intracellulary. First via actin, then to nesprin 1/2, all the way to nuclear membrane
- this can trigger lamin and chromatin inside the nucleus to change gene expression
WHY?
- it is another mechanism for rapid signaling from the plasma membrane
- allows it to respond to changes quickly in the environment that are more mechanical based than anything else
Laminopathies
- Emery-Dreifuss muscular dystrophy
- striated muscle
- Mutations in LINC genes inc. LMNA point mutation H222Y
- Muscle degeneration, weakness and atrophy; Cardiac defect - Dunnigan-type familial partial lipodystrophy
- adipose tissue
- Various missense mutations in
LMNA
- Adipose tissue redistribution, insulin resistant diabetes mellitus - Charcot-Marie-Tooth disease type 2B1
- peripheral nerve
- Recessive mutations in LMNA
- Motor and sensory neuropathy
- slight or absent reduction of nerve-
conduction velocities - Hutchinson-Gilford progeria syndrome
- progeria phenotype
LMNA deletion
- Early onset aging, alopecia, fragile
skin, atherosclerosis
Lamins in cancer
Lamin A or lamin C expression is downregulated in leukemias, lymphomas, breast cancer, colon cancer, gastric carcinoma and ovarian carcinoma
- Reduced levels of A-type lamins are predicted to result in more malleable nuclei, which could facilitate extravasation & invasion of malignant cells through narrow constrictions
Conversely…
- expression of A-type lamins is upregulated in skin and ovarian cancers
- higher lamin levels could support the increased mechanical stress within solid tumors
- changes in lamin expression could modulate cell proliferation, differentiation, epithelial-to mesenchymal transition and migration
