Cancer, stem cells, and cancer stem cells Flashcards
- Define tissue stem cells - Explain what is meant by the term "cancer stem cell" - Contrast the terms "tissue stem cell" and "cancer stem cell" - Theorise about the relationship of tissue stem cells to cancer cells of origin
Define stem cell
a cell which can self-renew and differentiate
What does it mean to differentiate a cell
to permanently alter the gene expression
What does it mean when a cell is described as being able to self-renew
the cell can divide and make a copy of itself with identical properties
Totipotent
can make everything
Pluripotent
can make all somatic cells
Multipotent
can make many different cell types
Bi-/Tri- etc. potent
2/3 etc. cell types
Unipotent
can only differentiate into one cell type
What is potency
- refers to the ability of a cell to change
- depends on how many types a stem cell can differentiate into
- usually restricted with developmental age/tissue restriction
Embryonic stem cells
- cultured in vitro derived from cells of the early embryo
- pluripotent -> can make all somatic cell types
- immortal -> indefinitely self-renew
Adult/tissue stem cells (somatic)
- exist in many (most?) tissues
- normally contribute to the tissue maintenance
- numbers, properties and functions vary enormously
General characteristics of somatic stem cells (NOT DEFINING CHARACTERISTICS!)
- rare
- slow cell cycle (divide infrequently)
- symnmetric or asymmetric cell division
- unspecialised
- present in many adult tissues
- usually respect germ layer boundaries (reports of trans-germ layer potential/multipotency (controversial))
Division of somatic stem cells
must divide exactly 50% of the time -> any deviation from this results in problems and imbalance which gets worse with every cell cycle
Stem cell regeneration
- “regeneration” = homeostasis + repair
- tissues with a natural turnover (blood, skin, etc.)
- “reserve cells” for injury repair (muscle)
- differences between organisms
- lineage restriction
Biology of cancer stem cells
- develop from normal stem cells that gain the ability to proliferate aberrantly and eventually turn malignant
- grown clonally into tumours
- have the potential to metastasize
- share many characteristics with normal stem cells
Stem cells and cancer
- cancers are caused by mutations
- somatic cells are often short-lived and post-mitotic
- mutations may accumulate in long-lived, proliferating cells
- cancer-causing mutations in stem cells or progenitor cells (all lineage of stem cells will carry that mutation)
Normal progression of stem cells vs cancerous progression of stem cells
Normal:
1) stem cell can self renew and differentiate into progenitor cell
2) progenitor cell can give rise to oligolineage precursors
3) growth into mature cells
Cancer in stem cells:
1) cancerous stem cell gives rise to cancerous progenitor cells
2) cancerous progenitor cells advance to mature cancer cells
Cancer in progenitor cells
1) healthy stem cell can self-renew and differentiate into progenitor cell
2) mutation in progenitor cell, cells become cancerous
3) give rise to mature cancer cells
Tomasetti et al, 2015
- hugely controversial
- take home message was that cancer is due to bad luck
- calculated number of stem cells in all tissues and the frequency of division to work out total number of divisions in any tissue
- plot this against lifetime risk of cancer in any tissue -> strong positive correlation
- therefore, more stem cells = more frequent division = likelihood of cancer increases
THIS IS NOT THE CASE!!! - paper actually states that it is down to luck whether cancer progresses IN THAT PARTICULAR ORGAN and there are numerous risk factors that are prompted in the graph (e.g. smokers)
- the more stem cell divisions in a tissue, more likely that tissue is prone to cancer. does not mean that stem cells cause cancer. stem cells divide INFREQUENTLY
Cancer stem cells
- Stevens and Little (1954)
- spontaneous testicular teratomas in inbred strains of mice
- tumours arise relatively frequently in humans
- tumours are well-differentiated; cell types represent all cell layers (arise from pluripotent cells)
- in a certain proportion, tumours are malignant
- cells are able to differentiate into all cell types
- these cells are stem cells of the tumour
Cancer stem cell beginnings
- some tumours of the reproductive organs contain a huge variety of different cell types
- teratomas / tetratocarcinomas
- strains of mice spontaneously get them at high frequency
- embyonal carcinoma cells
- can be transplanted and give rise to fresh teratocarcinomas
- single cells!
(Kleinsmith and Pierce, 1964)
Brief history of cancer and stem cells
- papers as far back as 1951 suggest that tumours are maintained by stem cells
- at the time the momentum was for radical surgery - lack of evidence for efficacy
- eventually these studies led to a change in the way we consider tumours
Cancer stem cell model
- not all cells in a tumour are the same
- a subset of cells are able to elaborate tumour heterogeneity
- numbers can vary
- cancer stem cell is not necessarily a tissue stem cell that got cancer
- CSC is a cancer cell with stem cell properties (e.g. self-renewal, differentiation capacity)
Supporting evidence
- not all tumours are tumourigenic (Southam et al (1966) autotransplanted tumour cells in patients
- cancers can differentiate: teratocarcinoma cells from chimeras
- these studies do not prove the model, prospective purification of CSC required
CSC in leukaemias
Lapidot et al (1994)
- AML cells in SCID mice
- expansion of AML-CFU but poor proliferation in vitro
- suggests a more immature cell present
- sorted cells to identify initiating cells
- only CD34+ CD38- cells could
- markers similar to HSC
- most likely early progenitor cells (CD90-)
CSC in solid tumours
Al-Hajj et al (2003)
- breast cancers
- CD44+ CD44- / low lineage - cells are tumourgenic in SCID mice
- 100 cells enough
- mouse tumours same heterogeneity as the originals
