BIOLOGY 2F03 Lecture Notes - Lecture 20: Cluster Of Differentiation, Metastasis, Somatic Evolution In Cancer
19 Jun 2018
School
Department
Course
Professor
Surgery and Anaesthesia Sheena Cheung ssc211
Module 1: Cancer repair and regeneration With additions from ABS’ notes
2
Over-expression of drugs resistance genes
o Regulated by similar pathways
Pathway
Stem cell self-renewal
Tumorigenesis
Wnt
Haematopoietic,
epidermal, gut
Colon carcinoma, epidermal
tumours
Sonic Hedge Hog
(Shh)
Haematopoietic, neural,
germline
Medulloblastoma, basal cell
carcinoma
Notch
Haematopoietic, neural,
germline
Leukaemia, mammary tumours
Only a small subset of cancer cells is capable of extensive proliferation: these are the cancer
stem cells
o 1 in 10,000 myeloma cells are able to form colonies in vitro
o Only 1-4% transplanted leukaemic cells could form spleen colonies in vivo
o A large number of cells are required to grow a tumour because only a few cells in those
millions of cells can sustain growth
o Markers of cancer stem cells are being used to isolate tumour sustaining cells from
tumours: e.g. CD24 (HAS), ABCG5, ALDH1 etc.
e.g. CD133+ cell surface marker are identified in brain tumour cells to be cancer
stem cell
Two general models for cancer heterogeneity
o CLONAL EVOLUTION MODEL: All cancer cells have the potential to be cancer stem cells
but have a low probability of proliferation in clonogenic assay, heterogenous behaviour
is due to extrinsic microenvironmental cues
o CSC MODEL: Only a small clearly definable subset of cancer are cancer stem cells that
have the ability to proliferate indefinitely
o Combined model: initial growth is driven by a CSC, but as the tumour progresses, clonal
evolution can be due to mutation and epigenetic modification. If this is more aggressive,
can become dominant and drive tumour formation.
Metastasis
If CSC model is to be believed, metastatic cancer cells that takes hold has to be migratory
cancer stem cells otherwise they won't proliferate in the distal cancers
PRC2 Polycomb repression complex 2 is known to repress gene transcription. If it binds to the
gene containing DNMT, it can switch genes off. Knock out of EZH1/EZH2 of DNMT gene with
PCR2 reduces proliferation.
Drug resistance
Gene vulnerability to hypermethylation
o Chromatin patterns and transient silencing of important regulatory genes in stem cells
can leave the genes vulnerable to damage
o Occurring during tumour initiation and progression
o Promotor chromatin patterns are bivalent: can be both permissive and repressive
Mix of chemosensitive (drug-tolerant poised state of CSC) and resistant subpopulation gives
rise to resistance
o Persistent epigentically poised state gives either chemo-sensitive or chemo-resistant
relapse
