DNA & Disease
The Biology of Cancer - Robert Weinberg
• Cancer results from the uncontrolled growth of cells in certain tissues in the human body
• 1 in 2 people in the UK get cancer
• Almost all species on the planet develop tumors. Except the naked mole rat, probably the only species
on the planet NOT to get cancer. Cells stick together better in these species, higher levels of HMMHI
Cancer results from:
• Current dogma – clonal origins of cancer
• mutations in DNA
• diet and lifestyle – tobacco, alcohol
• Epigenetic change – change in the expression in genes which can effect
cancer
• Cancer arises by successive mutations in a clone of proliferating cells. End up
with a range of mutations.
Evidence that cancers are clonal in origin
TUMOURS contain either type - Chronic Myeloid Leukaemia
A & B of the G6PD, never both
Normal tissue contains
both type A & B of G6PD
Modification of this theory - Mutations in STEM CELL PROGRAMMING!
Both normal and cancer cell populations have subpopulations of stem cells (SCs) that can both self-renew
and spawn more differentiated progeny.
There are 2 models - the involvement of stem cells (SCs) in
multi-step tumor progression can be depicted in two
alternative mechanistic schemes. Both schemes embrace the
notion that each participating cell population beginning with
fully normal cells and culminating in fully neoplastic cells
contains a subpopulation of SCs.
(A) In this scheme, one stem cell subpopulation, having
developed a heritable/genetic change such as a somatic
mutation, evolves directly into the next stem cell
subpopulation with no involvement of non-stem cells in this
multi-step process.
(B) An alternative scheme proposes that the heritable changes
in cell populations are initially acquired in non-stem cell
populations, specifically transit-amplifying cells, often termed
progenitor cells. Having acquired an advantageous change, progenitor cells introduce this change into a
stem cell subpopulation via a process of dedifferentiation. Therefore, stem cells change progressively
during multi-step tumor progression but are not themselves the initial sources of these changes. Rate of
division of stem cells is slower than differentiation cells. Therefore, mutation is nearly impossible.
,Cancer ‘Stem Cell’ hypothesis
Tumours, like adult tissues, arise from cells that exhibit the ability to self-renew as well as give rise to
differentiated tissue cells.
• Normal hematopoietic stem and progenitor cells (a). The HSC is a unique hematopoietic cell by virtue
of its ability to self-renew as well as generate all cells of the hematopoietic system.
• HSCs generate the multitude of hematopoietic cells by giving rise to MPPs and progressively lineage-
restricted progenitors that have limited capacity to divide. Leukemia stem and progenitor cells (b).
• Similar to the HSC, the LSC has the unique
ability to self-renew.
• LSCs give rise to clonogenic leukemic
progenitors that differentiate into leukemic
blasts and more differentiated progeny.
• Although the cell of origin of the LSC has not
been elucidated, investigators hypothesize
that LSCs arise from immature hematopoietic
progenitors or possibly the HSC.
• The arrows are drawn to indicate candidate
progenitor cells in which transformation.
What causes cancer
1. Diet and lifestyle - Exposure to mutagens / carcinogens
• Percentage of cancers attributed to excessive alcohol consumption and tobacco use.
Excessive alcohol use has been linked to liver and mouth/throat cancers in both males and females. Breast
cancer risk is high in females who drink to excess. Smoking and tobacco use significantly increases the risk
of lung cancers equally in males and females, and there is also a slightly higher risk of mouth/throat
cancers
2. Most cancers result from exposure to mutagens
• If one sibling or twin gets cancer, other usually does not
• Populations that migrate – profile of cancer becomes more like people indigenous to new location
3. Age
Most cancers result from aging. Although cancer can occur in persons of every age, it is common among
the aging population. Sixty percent of new cancer cases and two thirds of cancer deaths occur in persons >
65 years. The incidence of common cancers (eg, breast, colorectal, prostate, lung) increases with age.
4. Rare cancers run in families such as retinoblastoma
A tumor grows in the yes. But is easily removed
, Hallmarks of Cancer
1. Always on the ‘go’ - Most cells wait for a ‘Go signal before
dividing. Cancer cells don’t bother waiting… they produce
their own ‘Go’ chemical messages and continue dividing
(Overexpression of ONCOPROTEINS)
2. Bypass ‘stop’ signals - Even if the neighbouring cells
produce a ‘Stop’ signal, cancer cells override these signals
and continue dividing. (Inhibition OF TUMOUR SUPPRESSOR PROTEINS).
3. Ignore ‘slow down & die’ signals - Normal cells sometimes react to stress by triggering a ‘Self Destruct’
button and killing itself, but cancer cells sneak past these self-destruct signals and continue to divide, thus
accumulating more mutations. (Inhibition of pro-APOPTOTIC PROTEINS). Apoptosis usually kills the cancer
cells.
4. Increase food supply - Cancer cells stimulate growth of new
blood vessels by secreting growth factors (Overexpression of
ANGIOGENIC PROTEINS)
5. Divide, divide, divide - One of the key superpowers is
immortality. Unlike normal cells which have a finite life span,
cancer cells manipulate their own DNA (via repetitive DNA
sequences called telomeres) to keep dividing for a lot longer. (ACTIVATION OF TELOMERASES).
Telomerase protects the ends of chromosomes preventing them getting too short.
6. Escape immune security – immune cells attack the cancer cells. When they can’t cope cancer develops.
7. Invade & Spread - The lethal nature of cancer is due to its ability to spread to other location or
metastasize. 90% of cancer deaths are due to metastasis.
Emerging hallmarks
• An increasing body of research suggests that two additional hallmarks of cancer are involved in the
pathogenesis of some and perhaps all cancers.
• One involves the capability to modify, or reprogram, cellular metabolism in order to most effectively
support neoplastic proliferation.
• The second allows cancer cells to evade immunological destruction, in particular by T and B
lymphocytes, macrophages, and natural killer cells. Because neither capability is yet generalized and
fully validated, they are labelled as emerging hallmarks.
• Additionally, two consequential characteristics of
neoplasia facilitate acquisition of both core and
emerging hallmarks. Genomic instability and thus
mutability endow cancer cells with genetic alterations
that drive tumor progression.
• Inflammation by innate immune cells designed to fight
infections and heal wounds can instead result in their
inadvertent support of multiple hallmark capabilities,
thereby manifesting the now widely appreciated tumor-
promoting consequences of inflammatory responses.
, Intracellular signalling circuits in a cancer cell
• An elaborate integrated circuit operates within
normal cells and is reprogrammed to regulate
hallmark capabilities within cancer cells.
• Separate sub circuits, depicted here in differently
coloured fields, are specialized to orchestrate the
various capabilities.
• At one level, this depiction is simplistic, as there is
considerable crosstalk between such sub circuits.
• In addition, because each cancer cell is exposed to a
complex mixture of signals from its
microenvironment, each of these sub circuits is
connected with signals originating from other cells
in the tumour microenvironment
Tumours as complex tissues
Don’t look at cells in isolation.
