Leaning Objectives:
1. List the 10 hallmarks of cancer
2. Describe how the different hallmarks of cancer can be therapeutically targeted
3. Discuss how the different hallmarks of cancer influence cancer development
HALLMARKS OF CANCER
Cancer to be a disease involving dynamic changes in the genome.
The foundation has been set in the discovery of mutations that produce onco-genes with dominant gain
of function and tumor suppressor genes with recessive loss of function: both classes of cancer genes
have been identified through their alteration in human and animal cancer cells and by their elicitation
of cancer phenotypes in experimental models.
Many types of cancers are diagnosed in the human population with an age-dependent incidence
implicating four to seven rate-limiting, stochastic events. Pathological analyses of a number or organ
sites reveal lesions that appear to represent the intermediate steps in a process through which cells
evolve progressively from normalcy via a series of pre-malignant states into invasive cancers.
The genomes of tumor cells are invariably altered at multiple sites, having suffered disruption through
lesions as subtle as point mutations and as obvious as changes in chromosome complement.
Transformation of cultured cells is itself a multistep process: rodent cells require at least two
introduced genetic changes before they acquire tumorigenic competence, while their human
counterparts are more difficult to transform.
Observations of human cancers and animal models argue that tumor development proceeds via a
proves formally analogous to Darwinian evolution, in which a succession of genetic changes, each
conferring one or another type or growth advantage, leads to the progressive conversion or normal
human cells into cancer calls.
An Enumeration of Traits
The barriers to development of cancer are embodied in a teleology: cancer cells have defects in
regulatory circuits that govern normal cell proliferation and homeostasis. There are more than 100
distinct types of cancer, and subtypes of tumors can be found within specific organs.
Alterations in Cell Physiology that Dictate Malignant Growth:
1. Self-sufficiency in growth signals
2. Insensitivity to growth- inhibitory (antigrowth) signals
3. Evasion of programmed cell death (apoptosis)
4. Limitless replicative potential
5. Sustained angiogenesis
6. Tissue invasion and metastasis
Each of these physiologic changes represents the successful breaching of an
anticancer defence mechanism hardwired into cells and tissues.
a. Self-Sufficiency in Growth Signals
- Normal cells require mitogenic growth signals (GS) before they can
move from a quiescent state into an active proliferative state.
- These signals are transmitted into the cell by transmembrane
receptors that bind distinctive classes of signalling molecules:
, diffusible growth factors, extracellular matrix components, and cell-to-cell
adhesion/interaction molecules.
- As now known, no type of normal cell can proliferate in the absence of such stimulatory
signals.
- Many oncogenes in the cancer catalog act by mimicking normal growth signalling in one wat
or another.
- Tumor cells generate many of their own growth signals, thereby reducing their dependence on
stimulation from their normal tissue microenvironment.
- This liberation from dependence on exogenously derived signals disrupts a critically
important homeostatic mechanism that normally operates to ensure a proper behaviour of the
various cell types within a tissue.
- Three common molecular strategies for achieving autonomy are evident; involving alteration
of extracellular growth signals, of transcellular transducers of those signal, or of intra-cellular
circuits that translate those signals into action.
- While most soluble mitogenic growth factors (GFs) are made by one cell type in order to
stimulate proliferation of another (process of heterotypic signalling) many cancer cells acquire
the ability to synthesize GFs to which they are responsive, creating a positive feedback
signalling loop often termed autocrine stimulation.
- The manufacture of a GF by a cancer cell obviates dependence on GFs from other cells within
the tissue. Examples include; production of platelet-derived growth factor (PDGF) and tumor
growth factor α) TGFα.
- The cell surface receptors that transduce growth stimulatory signals into the cell interior are
themselves targets of deregulation during tumor pathogenesis. GF receptors, often carrying
tyrosine kinase activities in their cytoplasmic domains, are overexpressed in many cancers.
Receptor overexpression may enable the cancer cell to become hyperresponsive to ambient
levels of GF that normally would not tigger proliferation.
- Cancer cells can also switch the types of extracellular matrix receptors (integrins) they
express, favouring ones that transmit regrowth signals.
- The failure of integrins to forge extracellular links can impair cell motility, induce apoptosis,
or cause cell cycle arrest.
- Ras proteins are present in structurally
altered forms that enable them to release a
flux of mitogenic signals into cells, without
ongoing stimulation by their normal
upstream regulators.
- Growth signalling pathways suffer
deregulation in all human tumors.
- The downstream effector pathways that
radiate from the central SOS-Ras-Raf-MAP
kinase mitogenic cascade are being
discovered with some regularity. This
cascade is also linked via a variety of cross-
talking connections with other pathways;
these cross connections enable extracellular
signals to elicit multiple cell biological
effects.
- Many of the growth signals driving the proliferation of
carcinoma cells originate from the stromal cell components
of the tumor mass.
- Inflammatory cells attracted to sites of neoplasia may
promote (rather than eliminate) cancer cells, another
example of normal cells conscripted to enhance tumor
growth potential, another means to acquire necessary
capabilities.
1. List the 10 hallmarks of cancer
2. Describe how the different hallmarks of cancer can be therapeutically targeted
3. Discuss how the different hallmarks of cancer influence cancer development
HALLMARKS OF CANCER
Cancer to be a disease involving dynamic changes in the genome.
The foundation has been set in the discovery of mutations that produce onco-genes with dominant gain
of function and tumor suppressor genes with recessive loss of function: both classes of cancer genes
have been identified through their alteration in human and animal cancer cells and by their elicitation
of cancer phenotypes in experimental models.
Many types of cancers are diagnosed in the human population with an age-dependent incidence
implicating four to seven rate-limiting, stochastic events. Pathological analyses of a number or organ
sites reveal lesions that appear to represent the intermediate steps in a process through which cells
evolve progressively from normalcy via a series of pre-malignant states into invasive cancers.
The genomes of tumor cells are invariably altered at multiple sites, having suffered disruption through
lesions as subtle as point mutations and as obvious as changes in chromosome complement.
Transformation of cultured cells is itself a multistep process: rodent cells require at least two
introduced genetic changes before they acquire tumorigenic competence, while their human
counterparts are more difficult to transform.
Observations of human cancers and animal models argue that tumor development proceeds via a
proves formally analogous to Darwinian evolution, in which a succession of genetic changes, each
conferring one or another type or growth advantage, leads to the progressive conversion or normal
human cells into cancer calls.
An Enumeration of Traits
The barriers to development of cancer are embodied in a teleology: cancer cells have defects in
regulatory circuits that govern normal cell proliferation and homeostasis. There are more than 100
distinct types of cancer, and subtypes of tumors can be found within specific organs.
Alterations in Cell Physiology that Dictate Malignant Growth:
1. Self-sufficiency in growth signals
2. Insensitivity to growth- inhibitory (antigrowth) signals
3. Evasion of programmed cell death (apoptosis)
4. Limitless replicative potential
5. Sustained angiogenesis
6. Tissue invasion and metastasis
Each of these physiologic changes represents the successful breaching of an
anticancer defence mechanism hardwired into cells and tissues.
a. Self-Sufficiency in Growth Signals
- Normal cells require mitogenic growth signals (GS) before they can
move from a quiescent state into an active proliferative state.
- These signals are transmitted into the cell by transmembrane
receptors that bind distinctive classes of signalling molecules:
, diffusible growth factors, extracellular matrix components, and cell-to-cell
adhesion/interaction molecules.
- As now known, no type of normal cell can proliferate in the absence of such stimulatory
signals.
- Many oncogenes in the cancer catalog act by mimicking normal growth signalling in one wat
or another.
- Tumor cells generate many of their own growth signals, thereby reducing their dependence on
stimulation from their normal tissue microenvironment.
- This liberation from dependence on exogenously derived signals disrupts a critically
important homeostatic mechanism that normally operates to ensure a proper behaviour of the
various cell types within a tissue.
- Three common molecular strategies for achieving autonomy are evident; involving alteration
of extracellular growth signals, of transcellular transducers of those signal, or of intra-cellular
circuits that translate those signals into action.
- While most soluble mitogenic growth factors (GFs) are made by one cell type in order to
stimulate proliferation of another (process of heterotypic signalling) many cancer cells acquire
the ability to synthesize GFs to which they are responsive, creating a positive feedback
signalling loop often termed autocrine stimulation.
- The manufacture of a GF by a cancer cell obviates dependence on GFs from other cells within
the tissue. Examples include; production of platelet-derived growth factor (PDGF) and tumor
growth factor α) TGFα.
- The cell surface receptors that transduce growth stimulatory signals into the cell interior are
themselves targets of deregulation during tumor pathogenesis. GF receptors, often carrying
tyrosine kinase activities in their cytoplasmic domains, are overexpressed in many cancers.
Receptor overexpression may enable the cancer cell to become hyperresponsive to ambient
levels of GF that normally would not tigger proliferation.
- Cancer cells can also switch the types of extracellular matrix receptors (integrins) they
express, favouring ones that transmit regrowth signals.
- The failure of integrins to forge extracellular links can impair cell motility, induce apoptosis,
or cause cell cycle arrest.
- Ras proteins are present in structurally
altered forms that enable them to release a
flux of mitogenic signals into cells, without
ongoing stimulation by their normal
upstream regulators.
- Growth signalling pathways suffer
deregulation in all human tumors.
- The downstream effector pathways that
radiate from the central SOS-Ras-Raf-MAP
kinase mitogenic cascade are being
discovered with some regularity. This
cascade is also linked via a variety of cross-
talking connections with other pathways;
these cross connections enable extracellular
signals to elicit multiple cell biological
effects.
- Many of the growth signals driving the proliferation of
carcinoma cells originate from the stromal cell components
of the tumor mass.
- Inflammatory cells attracted to sites of neoplasia may
promote (rather than eliminate) cancer cells, another
example of normal cells conscripted to enhance tumor
growth potential, another means to acquire necessary
capabilities.
