Invasion - Regulation of cell migration Flashcards
Summarise the steps of tumour progression
Steps of tumour progression:
o Homeostasis- polarity of cell, cell-cell contacts intact, functions apropiately.
o Genetic alterations.
o Hyper-proliferation.- formation of benign tumour
o De-differentiation:
Disassembly of cell-cell contacts.
Loss of cell polarity.
o Invasion:
Increased motility.
Cleavage of ECM proteins.- formation of malignant tumour
Describe how metastasis requires distinct and sequential events
Epithelial cells in primary tumours are tightly bound together Metastatic tumour cells become mobile mesenchyme-type cells and enter the bloodstream. Metastatic tumour cells then travel through the bloodstream to a new location in the body. Metastatic cells exit the circulation and invade a new organ. Cancer cells (for unknown reasons) lose their mesenchymal characteristics and form a new tumour.
Describe the different types of migration
Individual cell migration:
o Amoeboid – e.g. lymphomas, leukaemia, SCLC
o Mesenchymal (single) – e.g. Fibrosarcoma, glioblastoma, anapaestic tumours
Collective cell migration:
o Mesenchymal (chains) – same as mesenchymal single
o Cluster/cohorts – e.g. Epithelial cancers, melanoma
o Multicellular strands/sheets – e.g. Epithelial cancers, vascular tumours
Collective cell migration requires more coordination to metastasise and so still has some cell-cell junctions, and to cleave more of the BM.
What do all metastasising tumours require
requires integrins for movement and proteases to digest ECM
What does collective cell migration require
Cadherins and gap junctions- to keep the cells as a cohort.
Cadherins drag neighbours along- taste regulator for differentiation (not usually expressed in invasive tissues- but needed for these cells to migrate together)
Describe how metastatic tumour cells mimic morphogenetic events
Cell growth in 2D sheet moving along ECM
Vascular sprouting in angiogenesis- with tip cells leading growth
Branching morphogenesis- maxillary gland - towards terminal end bud- for lactation- migration and differentiation of epithelium- maybe stromal signals
multicellular 3D strands and detached cluster -led by tip cells
border cells- nurse cells migrating as cluster to front of ovum to provide nutrients.
What is important to remember about tumour cell migration
Tumour cell metastasis/migration MIMICS PHYSIOLOGICAL morphogenic events.
o E.G. Branching morphogenesis in the mammary glands.
o E.G. Migration of primary glial cells to repair a scratch wound (the cells stop migrating when the contact is made) – conversely, tumour cells will have no clear migration front and no sense of direction.
They also lose contact inhibiton of locomotion, this is normally found in normal tissues so that they know when to stop growing
Describe an experiment which showed the the in vivo expression of invasive cell profile vs primary tumours using cDNA microarray profiling-gene expression
Needle collection of invasive cells (stimulated with EGF to direct growth)
FACS carcinoma cells from primary tumour- sequence these too
Invasive cells showed Upregulation of genes involved in:
Cytoskeleton regulation
Motility machinery
compared to the tumour cell
these cells were more likely to metastasise
remember- tumours are heterogenous.
State some stimuli for cell movement
organogenesis and morphogenesis
wounding
growth factors/chemoattractants
dedifferentiation (tumours)
How do the cells know where to go
directionality (polarity)
will change shape to grow towards stimulus- organelles directed towards direction of movement
How do migrating cells know when to stop
contact-inhibition motility
How do cells move
specialized structures (focal adhesion, lamellae, filopodium)
Describe the importance of regulation in this process
Regulation: required to coordinate stages, control adhesion/release of receptors and to respond to external influences
- What are the attachments between the cell and the surface that it is moving along called?
Focal adhesions
Integrins provide Attachment to substratum
(ECM proteins)
Cytoplasmic tails of interns have no enzymatic activity- so need to recruit a plaque of proteins to attach to filamentous actin- which will contract to move the cell towards the site of attachment. to the ECM at the focal adhesion- works like a hook.
Describe the importance of attachment to the substratum
Attachment to the substratum: cells require attachment to the ECM to allow response to growth factors and movement across tissue - filamentous actins terminate at focal adhesions to the ECM substratum - allowing to provide traction forces for movement
Describe filopodia
Finger-like protrusions rich in actin filaments
Used for motility
Vincluin important for formation
Describe lamellopodia
Sheet-like protrusions rich in actin filaments
Important for motility- throw membrane off to attach- then re-cycle membrane
Describe the importance of control of cell movement
within a cell to coordinate what is happening in different parts
regulate adhesion/release of cell-extracellular matrix receptors- adhesion and de-adhesion to grow towards stimulus- if they grew in all directions- cell would split apart.
from outside to respond to external influences –
sensors
directionality
Describe the two different types of movement
Motility: hapoptatic (random) versus chemotatic (direction and purpose)
