Previously we learned how cancer could be different and
unique – both between cancer types and even within the same tumor. And although these convolutions make
treatment of this disease a challenging task, cancer also shares some overarching
principles which help guide us in the identification of therapeutic targets. Today we will highlight these so-called
hallmarks of cancer. As a side note, this discussion also
serves as a good primer on cancer.
In the review article The
Hallmarks of Cancer (originally published in 2001, but updated in 2011),
two cancer research experts, Douglas Hanahan and Robert Weinberg comprised the
characteristics that underpin cancer and then summarized the research to
support their ideas. These
hallmarks, the features that almost all cancer cells acquire through the course
of tumor progression, have become so fundamental to the way scientists think
about cancer that they can actually drive the direction of our research. Obviously this article is required
reading for anyone interested in cancer research.
In this 3-part discussion, we will describe the 6 ingredients
that make up cancer as well as the 2 enabling
attributes that allow cancer to acquire these necessary traits. To help
visualize the process, I will provide simple signaling diagrams that highlight
key proteins involved in each process.
Figure 1: Hallmarks of Cancer (1)
For today’s discussion, we will highlight three traits that
are intimately linked:
Sustained Proliferative Signaling:
At its simplest, cancer is an overgrowth of cells, so
arguably without this trait, cancer would cease to exist. Mitogenic pro-growth signals including
growth factors or cytokines stimulate cell proliferation by binding to receptors
on the cell surface and triggering intracellular signaling pathways that
converge on the cell cycle. Under
normal, non-cancerous circumstances cells control their proliferation through
the restriction of growth signals or inhibition of the cell cycle. Cancer cells acquire several mechanisms
to overcome these obstacles. For
example, cancer cells themselves may release mitogenic (pro-growth) factors which
bind their own receptors (autocrine) or the receptors on neighbouring cells
(paracrine) to activate the cell cycle.
Furthermore, cancer cells may overexpress the receptor responsible for
relaying the growth signal into the cell.
The receptor Her2, amplified in a subsection of breast cancer patients,
highlights this phenomenon and we can now target this molecule with specific
therapeutics. Other key signaling
proteins involved in this process include several receptor tyrosine kinases
(RTKs) such as the EGFR receptor or Her2 as well as the downstream signaling
proteins RAS and PI3K and AKT.
Figure 2: Sustained Proliferative signaling. External mitogens (growth factors etc) bind to their cognate receptors such as Her2 or other receptor
tyrosine kinases (EGFR, MET, FGFR etc). These receptors relay signals into the
cell through interaction and alteration of downstream signaling proteins such
as PI3K or Ras which further transmits the signals down their respective
signaling cascades. Ultimately
these signals converge in the nucleus, the brain of the cell, where the cell
cycle is activated and/or pro-proliferative genes are transcribed. These newly synthesized genes could
include cell cycle proteins or mitogens which are released from the cell to
activate neighbouring (paracrine) cells or itself (autocrine).
Evading Growth Suppressors:
The decision to enter the cell cycle is made by tipping the
balance between pro-growth signals and the action of growth suppressors. Growth suppressors block
pro-proliferative signaling, acting as brakes on cell cycle progression. Through genetic mutations and/or loss
of function, cancer cells turn off these growth suppressors, thereby allowing
cell proliferation to proceed unchecked.
Often times these proteins and their encoding genes are referred to as
tumor suppressors since their loss of function can lead to the tumor formation.
Two of the most studied and important tumor suppressors for cancer development include
TP53 (p53) and RB.
Figure 3: Tumor Suppressors
p53 and pRb. In the nucleus, the tumor suppressor
p53 acts as a brake on cell proliferation through its function as a
transcription factor. When
activated, p53 increases p21 expression, a cyclin kinase inhibitor, or a
protein that inhibits cell cycle progression. The tumor suppressor pRb is inhibited by the pro-proliferative
complex Cyclin D/CDK4/6. However,
when activated pRB inhibits cell cycle progression by binding and inhibiting
the E2F transcription factor.
Resisting Cell Death:
Since cancer is fundamentally a product of excessive
proliferation, the concept that programmed cell death by apoptosis serves as a
natural barrier to cancer development is not surprising. Apoptosis, triggered by stressful
conditions such as excessive proliferation or DNA damage, protects cells from
spreading damage. The mechanisms
mediating this process have become clearer in the last decade. Furthermore, additional methods of cell
death including autophagy or necrosis have also been shown to play
important roles in mediating tumorigenesis. Specifically, the tumor suppressor TP53 plays a key role in
monitoring DNA damage and deciding whether a cell should divide or undergo
apoptosis. Other key players
include the caspases and the anti-apoptotic Bcl-2 family members.
Figure 4: Apoptotic
Signaling. In response to death signals,
the tumor suppressor and transcription factor p53 increases expression of
several pro-apoptotic proteins including Bax and Puma. These proteins congregate around the
mitochondria, or energy source, of the cell and cause the release of cytochrome
c. This activates the caspase
cascade and leads to DNA fragmentation, a hallmark of apoptosis.
Where do we go from
here?
By looking at the signaling diagrams, it is clear that these
three traits are intimately connected.
Sustained proliferative signaling is allowed to occur through the
evasion of growth suppressors such as the tumor suppressors p53 and pRb. Furthermore, by resisting cell death,
the accelerated cell proliferation program is allowed to accumulate. These connections
lie in the interplay between signaling pathways. For example, depending on the
stimuli, the tumor suppressor p53 (gene name TP53) can induce apoptosis through
upregulation of pro-apoptotic Bcl-2 family members or inhibit proliferation by
increasing expression of specific cell cycle inhibitors. Furthermore, pro-proliferative ERK can
inhibit activity of the growth suppressor pRB. Even without going into the intricate details, you can
already see how integrated and complicated cellular signaling pathways can
become. This kind of interplay between signaling molecules is a constant focus
in cancer research. Importantly, it
prompts the development of effective combination therapies which allow us to
target several pathways simultaneously.
Rationally, this should reduce the effects of drug resistance and tumor relapse.
Our next discussion will elucidate the roles of replicative
immortality, angiogenesis, and metastasis in cancer progression. Stay tuned!
References:
1. Hahahan D and Weinberg RA.
Hallmarks of Cancer Cell. 2001;100:57-70.
2. Hahahan D and Weinberg RA.
Hallmarks of Cancer: The Next Generation
Cell. 2011;144:646-74.
No comments:
Post a Comment