Investigations In Cancer Cell Biology Part V: Talking Cancer Tactics
The Enemy Within
What do you picture in your mind when you imagine war? Is it a soldier brazenly charging from behind a barricade, wearing a hefty machine gun at his waist, and relentlessly spraying lead towards his enemies? Perhaps it’s a different picture, one filled with mortar explosions, IED blasts, or gas-filled trenches. Whether it be due to Rambo movies or World War II lectures, these action-packed scenes dominate the civilian populace’s perception of war; however, the truth is that soldiers spend far less time in firefights on the battlefield and more time analyzing their enemies on sand tables. After all, if you do not understand your opponents’ capabilities, tendencies, and recent activities, how can you determine the defensive and offensive tactics necessary to defeat them? Sun Tzu, a famous Chinese General and author of The Art of War, once said, “if you know the enemy and know yourself, you need not fear the result of a hundred battles.”(Tzu, 221 B.C.E.)
Thus far in this Cancer 101 series, we have gotten to know ourselves by traversing the genetic concepts that underlie our physiology, and we have come to know the enemy as disruptive mutations that lead to destructive and overwhelmingly diverse tumors; however, we have not yet explored what cancer, our enemy, actually does. In this finale, we will wrap up our journey through the basics of cancer biology by discussing some of the first principles that define how cancer cells operate and maneuver to wage war against us.
Starting with concepts from Douglas Hanahan and Robert A. Weinberg’s 2000 publication, The Hallmarks of Cancer, we will explore cancer’s self-sufficient growth signals and insensitivity to antigrowth signals. Then, we will investigate Yousef Ahmed Fouad and Carmen Aanei’s propositions about cancer metabolism from their 2017 publication, Revisiting the Hallmarks of Cancer. Although we will not cover the countless other traits and habits that distinguish cancer cell biology, by understanding these three highlights, we will begin to understand cancer’s most defining feature: uncontrolled cell growth.
Figure 1: The Hallmarks of Cancer. “We suggest that most if not all cancers have acquired the same set of functional capabilities during their development, albeit through various mechanistic strategies.” (Hanahan & Weinberg, 2000)
Ultimately, cancer is a category of diseases characterized by uncontrolled replication; consequently, in order for a cancerous tumor to arise, that tumor must acquire the ability to increase its rate of cellular division. According to Hanahan and Weinberg, there are three main mechanisms through which cancer cells acquire this amplified ability to multiply: “extracellular growth signals…transcellular transducers of those signals…[and] intracellular circuits that translate those signals into action.”(Hanahan & Weinberg, 2000)
It is easy to picture this hallmark through the scope of how a theoretical farm would determine the amount of produce it needs to grow. The first factor in this analogy is the customers — analogous to the extracellular growth signals — who come to the farm and ask the cashier for more vegetables. If there is an abundant number of customers, then the farm will continue planting, harvesting, and multiplying its stock of vegetables to meet the demand. The next factor is the cashier, who, if dysfunctional, can incorrectly tell the other workers to ramp up production, even in the absence of an abundant demand for the products. Lastly, there are the farmworkers themselves, who can decide to plant, harvest, and multiply the farm’s products, regardless of whether or not they receive the appropriate messages from the cashier.
In terms of a cancer cell, the extracellular growth signaling molecules are similar to the customers at the farm, in that those molecules can increase the cell’s rate of division if they are abundantly available to bind with that cell’s transcellular transducers — receptors on the cell’s surface. The transcellular transducers are analogous to the cashier, in that they can receive signals outside of the cell and activate enzymes within the cell to induce cell division. Due to genetic mutation, these transcellular transducers can inappropriately over-activate those cascades of division-related enzymes and upregulate the cell’s rate of division. Finally, those cascades, or intracellular circuits, of division-related enzymes can become overactive themselves and upregulate the cell’s rate of division, despite not receiving the typically required activation from the transcellular transducers — similar to the overproductive farmworkers from the analogy above.
By leveraging any of these pieces in the growth signaling cascade, cancer cells can acquire self-sufficient growth signaling, meaning that they can upregulate their rate of cell division; however, they must surpass the second hallmark of cancer in order to achieve uncontrolled cell growth. Considering that there are over 1 quadrillion cell divisions in a human lifespan, it is incredible that we do not encounter dysfunctional growth more often, and we can attribute this to our cells’ abilities to balance growth signaling with antigrowth signaling.
Continuing with the farm analogy, antigrowth pathways are analogous to managers who regulate the farm’s productivity by limiting the number of customers that can come to the cashier and modulating the cashier and farmworkers’ activity levels. “Antigrowth signals can block proliferation by two distinct mechanisms.” said Hanahan and Weinberg, “Cells may be forced out of the active proliferative cycle into the quiescent (G0) state…Alternatively, cells may be induced to permanently relinquish their proliferative potential by being induced to enter into postmitotic states.”(Hanahan & Weinberg, 2000) In healthy cells, enzymes involved with antigrowth processes monitor their cell’s activity and halt or permit cell division by regulating the enzymes involved with propagating (the cashier) or responding to (farmworkers) growth signals. Depending on the conditions inside and surrounding the cell, these antigrowth pathways may put the cell into G0, or standby, where it is temporarily restricted from cell division; conversely, they may push the cell into a postmitotic state, or shutdown, where the cell can still function but is no longer allowed to divide. In cancer cells, mutations can remove or disrupt the enzymes responsible for antigrowth signaling, leaving the previously mentioned growth signaling cascades running rampant; additionally, some mutations can birth dysfunctional enzymes that prevent healthy extracellular antigrowth signals from impacting the cell’s ability to divide.
In other words, a cancer cell with self-sufficient growth signals is like a car with a dumbbell pressing down on its gas pedal, and a cancer cell with insensitivity to antigrowth signals is analogous to a car without brakes. Both hallmarks are natural but not infallible, necessary but not sufficient, and complementary but not complete in regards to cancer development; furthermore, they comprise only a third of the hallmarks that Hanahan and Weinberg believe, “are shared in common by most and perhaps all types of human tumors.”(Hanahan & Weinberg, 2000) Interestingly, it is only through acquiring all six of those hallmarks that cancerous tumors can achieve the dangerous complexity that we discussed last week, and it is these demanding requirements that Hanahan and Weinberg believe, “may explain why cancer is relatively rare during an average human lifetime.”(Hanahan & Weinberg, 2000) In this way, cancer really is a mirror of ourselves, in that the complex and adaptive nature of a malignant tumor is reflective of our complex and adaptive regulatory mechanisms that limit that tumor’s survival.
In 2000, Hannahan and Weinberg used the Hallmarks of Cancer to break down years of research on cancer’s intricate cellular biology into simplified first principles that physicians and scientists could use to target cancer’s overarching themes; interestingly, 17 years later, Yousef Ahmed Fouad and Carmen Aanei found during their continuation on the Hallmarks of Cancer that, “we have seemingly come full circle: from overwhelming complexity to anticipated simplicity, back again to substantial complexity.”(Fouad & Aanei, 2017) Their new assessment of the first principles driving cancer development maintains some of Hanahan and Weinberg’s ideas, such as altered growth and antigrowth signaling, while also proposing new hallmarks of cancer. Of these new propositions, how a cancer cell rewires its metabolism is one that is most relevant to the uncontrolled growth we discussed above.
Figure 2: “The Hallmarks of Cancer Revisited.”(Fouad & Aanei, 2017)
Considering that cancer cells exhibit hyperactivity and increased rates of cell division, it makes sense that they would require altered metabolism to fuel their productivity; yet, the manner in which they ramp up their energy systems is counterintuitive, in that they tend to upregulate the less efficient glycolytic pathways, instead of leveraging the more efficient aerobic pathways. In terms of the farm analogy, you can think of glucose — the simple sugar our cells break down for energy — as the money that the farm gets from customers and allocates towards producing their vegetables. Typically, the farm would allocate money toward plows and other machinery that, although requiring a larger investment, provide substantially more output than a worker hand-picking vegetables in the field; however, if the farm is dysfunctional, it may choose to allocate its funds differently. Imagine, like we discussed above, the farmworkers are inappropriately increasing the number of vegetables they plant, harvest, and multiply; consequently, the cashier now needs more tables at the farm stand and more packages for the vegetables. The dysfunctional farm may now allocate more funds towards hiring more farmworkers, instead of buying plows, in order to increase their production of tables and packages.
In a cancer cell, the mitochondria are similar to a plow on a farm, in that they require a large investment of breaking glucose down in the multi-step aerobic system but also offer a greater energy output than the less demanding glycolytic system. For this reason, scientists were surprised in the 1920s when Otto Warburg discovered that cancer cells preferentially utilize the glycolytic system over the mitochondrial aerobic system; however, modern cancer biologists propose that this makes sense if doing so, “provides means for continuous glucose shunting into intermediary pathways…[that produce] precursors or reducing equivalents indispensable to the tumor cell.”(Fouad & Aanei, 2017) Since cancer cells are rapidly dividing into new cells, they require an upregulation in the production of building blocks for the proteins and cell membranes that compose those new cells. “Cancer cells are characterized by a dramatic increase in lipid production with frequent upregulation of all major components of fatty acyl chain synthesis,” wrote Fouad and Aanei, “this may be advantageous to proliferating tumor cells in the formation of lipid bilayers, and also in alteration of membrane composition.”(Fouad & Aanei, 2017) So, similar to how an overactive farm would allocate its income to keep up with different aspects of its productivity, a cancer cell may utilize metabolic pathways that are less efficient from an energy production perspective but that are more beneficial in terms of rapidly building new cells. In addition to building more fatty acids for cell membranes, by ramping up their glycolytic pathways, cancer cells can increase their amino acid and nucleotide production as well.
In order for cancerous tumors to survive and prosper, they must not only upregulate their growth signaling pathways and suppress their antigrowth signaling pathways, but they must also alter their metabolic pathways to support their uncontrolled growth. Of course, at that point, the tumors still have yet to overcome the many other challenges to their existence, such as evading the immune system, traversing through harsh environments in different tissues of the body, building their own blood supply, and avoiding programmed cell death.
“Perhaps the key to cancer prevention would prove to be in the hands of understanding the hallmarks of normal cells and those of aging,” said Fouad and Aanei, “[and] linking them to the hallmarks of cancer, and attempting to break the link.”(Fouad & Aanei, 2017) It is possible that by exploring cancer tumors’ capabilities, tendencies, and recent activities — as well as those of our healthy cells — that we will be able to target the pathways and mechanisms enabling cancer to survive and disrupt our physiology; consequently, we will be able to flip the table and continue the previously mentioned cycle of adaptation, where cancer once adapted past our defenses and then forced us to adapt past its enhanced biological characteristics. In the words of Sun Tzu, “If you know yourself but not the enemy, for every victory gained you will also suffer a defeat. If you know neither the enemy nor yourself, you will succumb in every battle.”(Tzu, 221 B.C.E.)