Cancer Commonalities: The Hallmarks of Cancer Part 3

Welcome to the final discussion on the defining characteristics of cancer.  As we’ve discussed in parts 1 and 2 (Part1, Part2) cancer cells share several fundamental traits which are outlined in the figure below. 

Figure 1: Hallmarks of Cancer

In this final discussion, we take a step back:

What allows cancer cells to acquire these traits?  What allows cancer cells to tip the balance on all these processes towards tumorigenesis?  The answer begins with the following two enabling hallmarks. 

Genetic Instability

The acquisition of these 6 traits depends on a succession of alterations in the genomes of cancerous cells.  This increased susceptibility to genetic mutations is called genetic instability.  Normal cells possess remarkable capability to detect and resolve any DNA damage and mutations that might occur during cell division or through exposure to agents that cause mutations such as UV light.  However, cancer cells have increased rates of mutations as well as defects in the DNA damage sensors such that mutations go unchecked.  The guardian of the genome, TP53, which we have already encountered in its role as a tumor suppressor and in mediating apoptosis, is also central in maintaining genomic integrity.  Other caretaker genes include ATM and BRCA1/2. 

Figure 2: Caretakers of the Genome.  When DNA damage occurs, including mutations, DNA strand breaks etc, proteins sensors in the cell such as ATM recognize the damage.  If the damage is too severe, p53 is activated and the cell undergoes apoptosis, killing itself to prevent further damage.  If the damage is reparable, BRCA1/2 are activated and the damage is repaired so the cell cycle can continue.  In cancer cells that carry mutations in one of the caretaker proteins such as BRCA1/2, the damage is not repaired but the cell cycle continues, duplicating the mutation in daughter cells.  Such mutations inevitably lead to the accumulation of additional mutations and genetic instability. 

Tumor promoting inflammation

Like a bacterial infection, the presence of a tumor evokes an immune response.  When immune cells gather around a neoplastic lesion, they produce an inflammatory response, releasing bioactive molecules including growth factors to promote survival, proangiogenic factors to allow the growth of blood vessels, and extracellular matrix modifying enzymes to promote local invasion and metastasis.  Furthermore, immune cells also release chemicals such as reactive oxygen species which promote genetic instability.  Because inflammation can be detected at very early stages of tumor growth, researchers believe that this inflammatory immune response actually promotes tumorigenesis and the acquisition of additional tumor-bearing characteristics. 

Figure 3: Tumor promoting inflammation.  The presence of tumors can induce an inflammatory response by the immune system.  Immune cells recruited to the tumor site release cyokines and growth factors that can act on the tumor cell, enabling proliferation, migration, and angiogenesis  Additionally, the release of reactive oxygen species (ROS) can damage the DNA of cancer cells, leading to genetic instability. 

Where do we go from here?

Congratulations Readers!  You’ve completed your introduction to cancer biology! The 6 hallmarks of cancer and the two enabling traits comprise the foundation for understanding cancer at its most basic level.  You will see a lot of these characteristics and their key signaling proteins in future blog posts as we explore more exciting cancer research. 

For your reference, I’ve created a new tab that highlights the key proteins and their signaling pathways.  You can find them here. 

There’s a lot of information in these last three posts.  Although every attempt was made to be clear, it’s quite possible that some concepts aren’t fully understand.  Do you have any questions?  Is there something you’d like to know more about?  Let me know, and we can discuss it further or we can develop a new blog entry.   

The principle behind the hallmarks of cancer lies in the ability of cancer cells to tip the balance between normalcy and tumorigenesis.  With more research and better treatments, we hope to tip the scale back towards cellular homeostasis. 

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.