Unit 3 - Cell Biology of Cancer Flashcards Preview

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Flashcards in Unit 3 - Cell Biology of Cancer Deck (108)
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1

function of CTLA-4

brake on T-cell activation

functions to regulate T-cell activation

cancer cells benefit from reduced T-cell activation

MAb vs CTLA-4 releases the brake, allowing enhanced T-cell killing of tumour cells

2

PD-I

required for T-cell activation

acting through a different mechanism PD-I also acts as a brake on tumour-directed cells

MAb vs PD-I also 'releases the brake', allowing enhanced T-cell killing of tumours

3

use of MAbs

  1. MAb vs CTLA-4
  2. MAb vs PD-I

treatment with MAb has led to dramatic clinical outcomes - remissions and cures of metastatic cancers

  1. releases brake ⇒ enhanced T-cell killing of tumour cells
  2. releases brake ⇒ enhanced T-cell killing of tumour cells

4

CAR T-cell therapy

Chimeric Antigen Receptor

T-cells (specialised WBCs) are isolated from a patient and a custom designed gene, that expresses a new cells surface molecule that recognises the tumour and activates the T cell to kill it, is introduced into cells

cells containing the gene are grown in culture to prepare an inoculum

CAR T-cells are infused back into patient

T-cells target cancer cells for killing

5

MOA of CAR T-cell therapy

6

what is cancer

a disease that originates at the cellular level but tumoue function as complex tissues that integrate multiple cellular functions and mechanisms to promote tumour survival and growth

7

what is needed to identify the cellular origin of tumours

histology

8

how do cellular properties change as cancer develops/progresses

acquisition of adaptive phenotypes through mutation and genome instability couples with recruitment and modification of non-cancer cells to form tumour microenvironments

⇒ for diagnosis and prognosis + understanding therapeutics, knowledge of the cellular basis of cancer is good pragmatic knowledge (personalised therapy)

9

6 Hallmarks of Cancer

  1. sustained proliferative signalling
  2. evading growth suppressors
  3. activating invasion and metastasis
  4. enabling replicative immortality
  5. inducing angiogenesis
  6. resisting cell death

10

metastasis

migration of tumour cells from primary tumour to secondary sites

responsible for 90% of cancer deaths

11

how do cells spread

via blood, lymph and through proximity

12

where might secondary tumours form

lung, bone, liver, brain

lymph nodes

13

what are secondary tumours

tumours of primary tissue irrespective of tumour site

e.g. breast cancer within liver

histochemistry can identify tumour type and aid design of treatment

14

invasion-matastasis cascade - 7 steps

  1. localised invasion
  2. intravasation (into circulation)
  3. transport
  4. arrest (in a secondary location)
  5. extravasation (out of circulation and into tissue - colonisation)
  6. proliferation
  7. colonisation

utilise mechanisms related to pathways of embryonic development and wound healing

15

malignancy

penetration of tumour c ells beyond basement membrane id definitive of malignancy

16

EMT

epithelial → mesenchymal transition

change in phenotype

17

properties of epithelial cells

polygonal morphology

network of cell-cell junctions

apical-basal polarisation

limited mobility/motility

18

mesenchymal cells - properties

migratory

variegated morphology/spindle shaped

loosely organised

present in connective tissue/stromal tissue e.g. fibroblasts

19

key components of EMT

expression of embryonic transcription factors e.g. Snail, Slug, Twist, Zeb 1/2

loss of e-cadherin function

loss of tight junctions

acquisition of motility through CT

protease secretion

growth factor receptor expression

20

EMT - change in markers

Epithelial cells express epithelial markers and do not express mesenchymal markers

Twist - down regulation of epithelial cell markers and upreg of mesenchymal markers

21

anchorage-dependent signalling

E-cadherin

functions as a cell adhesion molecule

Maintains epithelial cell phenotype by signalling cell-cell interactions via IC domain

loss leads to dysregulation of β-catenin, a transcription factor regulated by localisation in the cell

22

β-catenin

integrated into cadherin-actin adherens junctions complexes

a normal component of Wnt signaling pathway

upon loss of cell adhesion it translocates to nucleus to activate TCF/LEF family transcription factors - loss causes cell to move into a different phenotypic state

regulated by molecular association e.g. E-cadherin and APC and by inhibitors e.g. ICAT (inhibition of β-catenin and TCF4)

cytoplasmic levels are maintained through ubiquitin-dependent proteolysis via the β-catenin destruction complex

mutation/misexpression correlated with cancer progression

23

familial adenomatous polyposis

proliferation of polyps in colon

1 in 30,000

24

APC gene

function = regulation of β-catenin through the proteolytic pathway

tumour suppressor gene

autosomal dominant mutations

maintains epithelial cell phenotype in colonic crypts

integrates cellular architecture, motility with cell cycle regulation and gene expression

also functions in mitosis and loss contributes to CIN

(cells live for 4 days)

25

transcription factors and metastasis

especially embryonic TFs

regulate differentiation and de-differentiation

Tcf/Lef, Slug, Snail

26

cell surface receptors and metastasis

EGF

E-cadherin

27

motility regulating proteins and metastasis

GTPases, PI3K and PIP3

cytoskeleton proteins

28

EC proteases

matrix metalloproteases break down EC matrix providing space to move

mesenchymal type cells

29

progression of EMT

30

invasion-metastasis cascade

LOCALISED INVASION

EMT

motility

proteases