The Hallmarks of Cancer – Insights from Decades of Research

The Hallmarks of Cancer - Insights from Decades of Research - 1

Introduction

Cancers are complicated. Many people try to envision and promote simple, one-shot approaches towards better management. Others engage in magical thinking by saying it’s a conspiracy not to cure it. Cancer physician and Pulitzer winner Siddhartha Mukherjee makes a compelling case for the complexity of cancers in this recent NYT issue (long read).

Even though each cancer has its unique characteristics – at least from a genomics point of view – there are a couple of similarities that have been observed in most forms of cancers.

Published in 2000 and updated in 2011, The hallmarks of cancer [1, 2] is a paper that has gathered more than 20,000 citations according to Google Scholar.

Reading the paper(s) allows you to grasp the complexity of cancers and how ‘reductionist’ it is to approach management with single strategies (such as chemo-, diet, radio-, HBOT, fasting, other agents and therapies).

In my opinion, a multi-factorial intervention would make more sense, especially in light of the 6-8 hallmarks described by Douglas Hanahan and Robert Weinberg (2011) [2] in their paper(s). Here I will present each of these hallmarks briefly.

The Hallmarks of Cancer

In their first paper [1], published in 2000, Hanahan and Weinberg highlighted the following “six biological capabilities acquired during the multistep development of human tumors” [2] (see figure at the top of the page for a graphical representation):

  1. Sustaining proliferative signaling
  2. Evading growth suppressors
  3. Resisting cell death
  4. Enabling replicative immortality
  5. Inducing angiogenesis
  6. Activating invasion and metastasis.

Underlying these hallmarks are genomic instability and inflammation. The advance of technology and the increase in clinical and research data have added two more emerging hallmarks to the list:

  1. Reprogramming of energy metabolism
  2. Evading immune destruction

The Hallmarks of Cancer - Insights from Decades of Research - 2

Let us move, summarily, through each of them.

  1. Sustaining Proliferative Signaling

Hanahan and Weinberg consider this hallmark as one of the most fundamental traits of cancer cells [2]:

“Cancer cells can acquire the capability to sustain proliferative signaling in a number of alternative ways: They may produce growth factor ligands themselves, to which they can respond via the expression of cognate receptors, resulting in autocrine proliferative stimulation. Alternatively, cancer cells may send signals to stimulate normal cells within the supporting tumor-associated stroma, which reciprocate by supplying the cancer cells with various growth factors”

  1. Evading Growth Suppressors

Additionally to the first hallmark, cancer cells must also evade negative regulation of cell proliferation – which is mostly done by tumor suppressor genes:

“The two prototypical tumor suppressors encode the RB (retinoblastoma-associated) and TP53 proteins; they operate as central control nodes within two key complementary cellular regulatory circuits that govern the decisions of cells to proliferate or, alternatively, activate senescence and apoptotic programs.” [2]

Malignancy is also promoted by the corruption of TGF-b pathway:

“TGF-b is best known for its antiproliferative effects, and evasion by cancer cells of these effects is now appreciated to be far more elaborate than simple shutdown of its signaling circuitry.” [2]

  1. Resisting Cell Death

The intricacies of the different mechanisms of cell death resistance seem unthinkable:

“The autophagic program enables cells to break down cellular organelles, such as ribosomes and mitochondria, allowing the resulting catabolites to be recycled and thus used for biosynthesis and energy metabolism.” [2]

And more striking (I would have never thought of this):

“Perhaps paradoxically, nutrient starvation, radiotherapy, and certain cytotoxic drugs can induce elevated levels of autophagy that are apparently cytoprotective for cancer cells, impairing rather than accentuating the killing actions of these stressinducing situations.” [2]

Hanahan and Weinberg also discuss about a survival response of cancer cells [2]:

  1. Stressed cancer cells shrink via autophagy, leading to a state of reversible dormancy
  2. They re-grow after anti-cancer treatment.

“Thus, in analogy to TGF-b signaling, which can be tumor suppressing at early stages of tumorigenesis and tumor promoting later on, autophagy seems to have conflicting effects on tumor cells and thus tumor progression…

An important agenda for future research will involve clarifying the genetic and cell-physiologic conditions that dictate when and how autophagy enables cancer cells to survive or causes them to die.” [2]

  1. Enabling Replicative Immortality

To become macroscopic tumors, cancer cells need unlimited replicative power. To achieve this, they need to bypass [2]:

  1. Senescence – irreversible step to a non-proliferative state
  2. Crisis – cell death
  1. Inducing Angiogenesis

To grow, cancer cells need nutrients, oxygen, “as well as an ability to evacuate metabolic wastes and carbon dioxide.” [2]

  1. Activating Invasion and Metastasis

Hanahan and Weinberg describe this process (particular to certain cancer cells) [2]:

  1. Local invasion
  2. Intravasation – into nearby blood and lymphatic vessels
  3. Transit of cancer cells through the blood and lymphatic systems
  4. Extravasation – escape into the parenchyma of distant tissues
  5. Micrometastases – the formation of small nodules of cancer cells
  6. Colonization – growth of micrometastatic lesions into macroscopic tumors.

Metastasis is aided by reversible dormancy (see above) and two other mechanisms (emerging hallmarks):

  1. “Major reprogramming of cellular energy metabolism in order to support continuous cell growth and proliferation, replacing the metabolic program that operates in most normal tissues and fuels the physiological operations of the associated cells.
  1. Active evasion by cancer cells from attack and elimination by immune cells; this capability highlights the dichotomous roles of an immune system that both antagonizes and enhances tumor development and progression.” [2]
  1. An Emerging Hallmark: Reprogramming Energy Metabolism

Here they describe normal cell vs. cancer cell metabolism (observed in several forms of cancers, not all):

– in the presence of O2, normal cells process glucose => to pyruvate via glycolysis in the cytosol => CO2 in the mitochondria;
– in the absence of O2, glycolysis is favored => little pyruvate enters the mitochondria.

On the other hand, even when there is O2, cancer cells can reprogram their energy production in favor of glycolysis (often termed ‘aerobic glycolysis’):

“Such reprogramming of energy metabolism is seemingly counterintuitive, in that cancer cells must compensate for the 18-fold lower efficiency of ATP production afforded by glycolysis relative to mitochondrial oxidative phosphorylation.” [2]

This happens, partially, by upregulating GLUT1 => increased glucose transport inside the cell.

With accentuated glycolysis often comes oncogene activation (RAS, MYC, etc.) and mutant tumor suppressors such as P53, “whose alterations in tumor cells have been selected primarily for their benefits in conferring the hallmark capabilities of cell proliferation, avoidance of cytostatic controls, and attenuation of apoptosis.” [2]

Glucose dependence can be enhanced in hypoxia (seen within many tumors).
Hypoxia => upregulation of glucose transporters and several glycolysis related enzymes.

  1. An Emerging Hallmark: Evading Immune Destruction

“The long-standing theory of immune surveillance proposes that cells and tissues are constantly monitored by an ever-alert immune system, and that such immune surveillance is responsible for recognizing and eliminating the vast majority of incipient cancer cells and thus nascent tumors.” [2]

The Hallmarks of Cancer - Insights from Decades of Research - 3

  1. Stroma of primary tumors creates a supportive microenvironment for cancer cells
  2. When released into circulation and reaching distant organs, cancer cells encounter a normal (healthy) microenvironment
  3. Similar (to primary tumor site) interactions between cancer cells and stromal cells have to happen in the new microenvironment to support cancer colonization of the new site.

“Although this logic applies in some cases of metastasis, in others, as mentioned earlier, certain tissue microenvironments may, for various reasons, already be supportive of freshly seeded cancer cells; such permissive sites have been referred to as metastatic niches.” [2]

I attended a lecture on this exact subject. It was presented by Stanford’s Prof. Philip Beachy, at MSKCC in NYC in May 2016. Unfortunately, I see MSKCC haven’t uploaded it to their media channels. I found a similar past lecture (along the same lines) from Prof. Beachy, presented in 2010.

Concluding thoughts

Here’s a graphical representation of some of the currently used/proposed strategies to target one or more of the hallmarks discussed above [2]:

The Hallmarks of Cancer - Insights from Decades of Research - 4

As they carefully point out, one therapy targeting a specific hallmark may not kill all cancer cells, “allowing some cancer cells to survive with residual function until they or their progeny eventually adapt to the selective pressure imposed by the therapy being applied.” [2]

This type of adaptation can occur through remodeling of the stromal microenvironment, through mutation, and through epigenetic reprogramming. Hence, cancer cells can reestablish their functional capacity => regrowth of tumor, relapse. Hanahan and Weinberg (2011) [2] think that such adaptive resistance can be prevented by targeting all pathways supporting a hallmark (as their number may be limited). They conclude their paper – optimistically reserved – by saying:

“Looking ahead, we envision significant advances during the coming decade in our understanding of invasion and metastasis. Similarly, the role of aerobic glycolysis in malignant growth will be elucidated, including a resolution of whether this metabolic reprogramming is a discrete capability separable from the core hallmark of chronically sustained proliferation. We remain perplexed as to whether immune surveillance is a barrier that virtually all tumors must circumvent, or only an idiosyncrasy of an especially immunogenic subset of them; this issue too will be resolved in one way or another.” [2]

Much has happened since 2011, especially within the fields of genomics, immunotherapy (really promising), imagining, and metabolomics. Thus, I think it would be fair to expect another update on this compelling work soon; an update that will advance better and more powerful approaches towards the management and prevention of cancers.

References:

  1. Hanahan, D., & Weinberg, R. A. (2000). The hallmarks of cancer. Cell, 100(1), 57-70.
  1. Hanahan, D., & Weinberg, R. A. (2011). Hallmarks of cancer: the next generation. Cell, 144(5), 646-674.

Images: here


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