Summarisation- Hallmarks of Cancer the Next Generation
The Hallmarks of Cancer is a peer reviewed article by Douglas Hanahan and Robert Weinberg
(H&W) published in 2000 in the journal Cell. At the time, research into the many diseases that fall
under the bracket of cancer was limited, and so they sought to simplify the complexities of the disease
into the following six common principles, thought to govern the transformation of normal cells into
tumours and/or malignant cancers: sustaining proliferative signalling; evading growth suppressors;
resisting cell death; enabling replicative immortality; inducing angiogenesis and activating invasion
and metastasis
It became the most cited paper published by Cell and was widely recognized and credited by many
experts. A decade of further research resulted in the article being updated in 2011 with two more
‘emerging hallmarks’: reprogramming of energy metabolism and evading immune destruction. H&W
also added two ‘enabling characteristics’ that they argued underlie all of eight of these principles:
genome instability and inflammation. These do not necessarily cause cancer but assist cells in a
transition from normal to oncogenic.
Cancer is the deregulation of normal cell control mechanisms, such as those of proliferation,
senescence and apoptosis which causes cells to uncontrollably divide and form benign tumours which
can become malign and invasive.
2000 – Original Six Hallmarks
Cell proliferation is the increase of cell numbers in relation to the balance between cell divisions and
loss. In tumours, cells enter a constant proliferative state where this balance is skewed towards cell
division by changes in cell signalling pathways. Changes vary from autocrine signalling, with an
increase in production of growth factor and expression of cognate receptors, to paracrine signalling,
where neoplastic cells stimulate neighbouring normal cells to supply elevated levels of growth factor.
In addition, an increase in the number of receptor proteins can cause cells to become hyper-responsive
to growth factor as well as structural changes to such receptors, causing independent signalling.
Lastly, various changes to downstream, intracellular pathways can render cells independent to growth
factor signalling; however, this is poorly understood.
The cell cycle is normally moderated by growth suppressors, which either slow down or halt
transition between certain cell cycle phases (eg. G1/S transition). H&W focus on the evasion of two
of these proteins: RB (retinoblastoma-associated) and TP53. The role of RB is to integrate
extracellular and intracellular growth signalling and regulate the growth-and-division cycle of a cell.
By remaining bound to transcription factors needed for activation of genes essential for transition
from the G1 phase to S phase, it prevents cell division. Conversely, TP53 detects stress and abnormal
signalling from exclusively inside the cell eg. DNA damage, lack of glucose/oxygenation and growth
promoting signals. TP53 either halts cell cycle until normalized or induces apoptosis if unfixable.
Mutations in the genes coding for these growth suppressors results in a reduced or lack of function of
these proteins; therefore, speeding up the cell cycle.
Apoptosis is the main form of programmed cell death and a natural barrier to cancer by preventing
