Conquering the Biological Politics of Cancer: Corruption, Coercion and Collusion

January 3, 2018

Understanding the “Three C’s” may provide the insights need to move the needle on the cancers with the bleakest prognoses.

Broadly speaking, cancers fall into three categories: leukemias, brain tumors and other solid tumors. Since the dawn of chemotherapy in the 1940s, we’ve converted the most common type of leukemia, acute lymphoblastic leukemia, from incurable to over 95 percent of patients now cured. We’ve also made great progress in other cancers that tend to be localized and thus amenable to surgery and/or radiation, such as retinoblastoma, Wilms tumor of the kidney, low grade brain tumors and Hodgkin’s lymphoma. For all of these diseases, we now achieve greater than 80 percent survival. Even for highly malignant sarcomas such as Ewing sarcoma, osteosarcoma and rhabdomyosarcoma, survival rates are at or above 70 percent for localized cancer. When these cancers are metastatic, however, survival rates have remained flat for decades. We are only able to save 1-3 patients out of 10. Why?

Most of cancer research to date has been based on the idea is that all we need to do is figure out the vulnerabilities of cancer cells and destroy them with our treatments. Thus, we’ve cultured cancer cells in a dish and searched for drugs that destroy them. We’ve also implanted cells on the backs of mice and, after a single small tumor forms, tested drugs in the mice to find those that shrink the tumors.

We now understand many of the tricks cancers use to evade our treatments, and these aren’t being captured very well in the dish or the mouse. First, cancer cells are corrupt compared with normal cells. They may acquire changes in the structure of some of their genes, which I call hardware corruption, or changes in the location, timing, and/or amounts of expression of normal genes, which I call software corruption. Pediatric cancers fall into the latter category. Worse yet, each time a cancer cell divides it becomes more corrupt, finding new ways to grow and spread faster and better. This means that the cells in a leukemia or in a tumor mass differ from each other and each site of metastasis differs from the others. Thus, in patients with metastases, in essence we may be treating 10s or 100s or even thousands of different cancers. And when we study those cells in the lab, they are likely corrupted in ways different from when they were growing in the person, making the findings from the lab fundamentally flawed and misleading. Furthermore, much of the current excitement of so-called targeted therapies may eventually fade because they are specific for certain corruptions that may not be present in every cell.

Second, cancers coerce normal molecules and cells to work for them. They recruit cells into their midst that normally repair wounds or prevent autoimmunity and use them to grow better and protect them from immune attack. We used to think cancers are 100 percent tumor cells, but now we know they also are mixtures of many different types of normal cells that aid and abet the cancer. When we study cancer cells in the laboratory dish, they don’t have these normal cells to help them. Again, the result of such lab tests may have us barking up the wrong tree.

Finally, different sites of cancer within the body collude with one another. Cancer masses trade information through the blood stream and/or lymphatic channels by passing cells and molecules to each other. If one site develops a supercharged, highly corrupted cancer cell, it can pass it to all of the other metastatic sites. If one site has cells producing large amounts of an important chemical for cell growth or a molecule that suppresses immune attack, it can share it with the other sites. Studying cells in a dish or isolated masses growing in a mouse doesn’t take this collaboration into account, giving us false hope about treatments that work in that setting but not in metastatic patients.

So far, we’ve mostly conquered the low hanging fruit of cancer by testing new treatments on isolated tumor cells growing in a dish or as a single mass in a mouse. If we want to make similar progress for more advanced cancers, we need to figure out ways to address their corruption, coercion and collusion.

I had the honor and pleasure of discussing the 3C’s of cancer at TEDxColumbus 2017. For more about the challenges and opportunities we face, see the video below.


Image credit: Jeffery S. Cripe