“This particular nurse said, cancer cells are those which have forgotten how to die. I was so struck by this statement.” — Harold Pinter
(The author thanks Dr. Michael Dwinell of the Medical College of Wisconsin for his assistance on this post.)
Hearing a doctor say the words “I am sorry, but you have cancer” is terrifying. I know. What is even more terrifying is hearing that the cancer has spread to a lymph node or another organ. Unfortunately, I know that sensation as well. As with almost any other cancer patient, hearing those words makes one wonder about the ability of the brilliant and selfless scientists undertaking cancer research to develop a drug to stop metastasis – the spread of cancer.
I. The Spreading and Staging of Cancer:
a) Cancer that has Spread is Called Metastatic Cancer.
Cancer starts when cells in a part of the body begin to grow out of control and, instead of dying, they form new cells that are abnormal. As the National Cancer Institute’s website explains, cancers frequently manifest themselves in the form of tumors, that is, abnormal masses of malignant cells that divide more than they should or do not die when a healthy cell would die. This definition is consistent with the quote, found at the beginning of this post, by Harold Pinter, who died of cancer in 2008 at age 78.
The spreading of cancer is called “metastasis.” Specifically, it is the movement of cancer cells from their initial site of growth, frequently called the primary site, to other tissue or organs or to the bones. For example, the liver is the main tissue site into which colon cancer cells move during metastasis. In a well explained and diagrammed article on its website, the American Cancer Society explains that and how cancer cells generally first spread into the lymph nodes and often then spread through the bloodstream. The liver, the lung, and the bones are common targets when cancer cells metastasize. In its discussion of metastasis, the National Cancer Institute states that it is important to understand that a cancer that has invaded another organ or tissue or the bones is still the original cancer. For example, colon cancer that has metastasized to the liver is still colon cancer, not liver cancer. Cancer that has spread to the lymph nodes, tissues, or organs close to the primary site is often called “local or regional metastasis.” Cancer that has spread to organs or tissues that are farther away is frequently referred to as “distant metastasis.”
b) The “Staging” of Cancer.
Whether cancer has spread or metastasized is critical information. The spreading of cancer is associated with a worsening prognosis, a point discussed by the American Cancer Society. With most cancers, doctors use a “staging” nomenclature as an indication of severity, which is discussed by the National Cancer Institute. This staging system is directly correlated with the distance that the tumor cells have spread away from the primary site of the cancer.
Stage I and Stage II cancers still reside in the initial tissue. For instance, using colon cancer as an example, Stage I and Stage II cancers reside in the colon. Cancer cells which have spread to lymph nodes generally are considered Stage III. Stage III is often called “locally advanced” cancer. Cancer cells which have spread even farther from the primary tumor site, such as to another organ, typically are known as Stage IV. Staging is discussed in a way understandable to lay persons in many websites, including the American Cancer Society’s site and the National Cancer Institute’s site.
To understand the potential seriousness of Stage IV cancer, one should know that there is no Stage V. Thus, Stage IV cancer is the most serious stage. (That said, there are differences in the severity or extent of Stage IV cancer.) This staging system is a general overview and oncologists have established guidelines for the expected varying levels and degrees within each stage dependent upon the severity or extent of the cancer spread.
Metastatic cancer, therefore, is cancer that has spread from the place where it originated, the primary site, to another place in the body. The National Cancer Institute explains that a tumor formed by metastatic cancer cells is called a metastatic tumor. It sometimes is simply referred to as a metastasis.
As alluded to above, the ability of an oncologist to treat metastatic cancer, that is, cancer that has progressed to Stage III or Stage IV, is challenging. Treating such advanced cancer is difficult for many reasons, but, according to Dr. Michael Dwinell of the Medical College of Wisconsin, who has undertaken extensive research in this particular area, the main reasons are 1) the process whereby the cancer cell moves into nodes or other distant tissues is still poorly understood; and 2) there are almost no known drugs approved for patient use that specifically target the cellular machinery that controls the mobility of cancer cells as they move from one organ into the lymph nodes, the bones, or other distant tissues.
II. Treating Metastastic Cancers:
Oncologists are familiar with the difficulties of treating advanced stage or metastatic cancers. Indeed, as is noted in an article entitled “Cancer Metastasis Scrutinized” that has been published in a scientific journal, it is well known to those involved in the treatment of or research into cancer that 90% of all cancer deaths are due to tumor metastasis. The American Cancer Society’s website discusses, in a clear manner, the complications of metastatic cancer. Dr. Dwinell has explained to this author that, while a lot of important information has been gathered on the genes, proteins, and processes that control cell growth and lead to the formation of tumors, there has been an alarming lack of headway on understanding how those cancer cells invade the surrounding tissues and eventually metastasize.
a) The “Seed and Soil” Theory of Metastasis.
The initial thoughts regarding metastasis were developed over one century ago, in the late 1800s, by Dr. Stephen Paget. Although detailed in an article in a respected journal, Dr. Paget developed what became known as the “seed-and-soil” hypothesis, which postulates that the cancer cell is considered the “seed” and the distant tissues the “soil.” The hypothesis is summed up by the idea that the cancer cells gain access to and move about the body through the blood system but that they only grow in those distant tissues with a conducive microenvironment, that is, where the “soil” is just right, for metastatic disease development.
b) Recent Discoveries on Metastasis.
Dr. Paget’s “seed and soil” theory was largely the extent of the scientific understanding of metastases until 2001, at which time researchers discovered that tumor cells had a critical protein that allowed them to move about the body in response to a second protein produced in the metastatic target tissue. In this model, using colon cancer (again) as an example, the colon cancer cells possess the 1st protein, which is called CXCR4. The liver cells make and release the 2nd protein, which is called CXCL12. That 2nd protein can enter into the bloodstream. Cancer cells in the blood can move to the liver – that is, metastasize – when CXCL12, which may have entered the bloodstream, comes into contact with CXCR4. For further discussion of this model, please see http://www.ncbi.nlm.nih.gov/pubmed/21990345 and http://www.sciencedaily.com/releases/2011/10/111010173011.htm. Additional proteins have subsequently been shown to participate in metastasis, but research suggests that CXCR4 plays a critical role in directing, much like a symphony conductor, the movement of cancer cells to specific metastatic destinations, such as the liver and bone marrow.
Based on the above findings, it was presumed that it might be possible to develop a drug or other agent that will block or interfere with CXCR4’s interactions with CXCL12 – and thus decrease metastasis. Unfortunately, Dr. Dwinell reports that, as of today, no FDA-approved candidate drug has proven clinically effective in accomplishing such interference needed to block metastasis.
c) Ground-Breaking Research at the Medical College of Wisconsin on Blocking Metastasis.
The Medical College of Wisconsin is one of the leaders in research on metastasis. Dr. Dwinell, Associate Professor and Director of the Bobbie Nick Voss Laboratory for Colon Cancer Research at the Medical College of Wisconsin, was one of the first scientists to discover that both normal colon cells and colon cancer cells have the CXCR4 protein. Dr. Dwinell also discovered that the normal colon cells also expressed the 2nd protein, CXCL12, but the cancer cells did not. Over the past 10-years, Dr. Dwinell and his team of researchers at the Medical College of Wisconsin have discovered that the absence of the CXCL12 protein from cancer cells may play a significant role in contributing to metastatic spread. The absence of CXCL12 production by cancer cells suggested to Dr. Dwinell and his team that perhaps this was a signature or hallmark of actively metastatic cells. Dr. Dwinell and his lab discovered that when cancer cells express BOTH Protein 1 (CXCR4) and Protein 2 (CXCL12) together, metastasis is much, much lower, than cells that only have Protein 1.
While more research needs to be done, it appears to Dr. Dwinell and his research team that when cells express Protein 1 in the absence of Protein 2, they are more likely to metastasize. If they express both Protein 1 and Protein 2, metastasis appears to be thwarted. Thus it is likely that Protein 1 (CXCR4) and Protein 2 (CXCL12) essentially provide a check-and-balance on metastasis. In a series of “add-back” experiments, Dr. Dwinell has since confirmed that the insertion of the missing Protein 2, CXCL12, through gene-therapy or a biological injection, can effectively block metastasis. Interestingly, and to the delight of the researchers, the link between Protein 1 (CXCR4) and Protein 2 (CXCL12) was shown to inhibit metastasis not only of colon cancer, but also breast cancer, melanoma, and, more recently, pancreatic cancer.
Dr. Dwinell has recently obtained a patent which enables him to try to develop a therapy that uses CXCL12, and its metastasis blocking abilities, to prevent the metastasis of cancer cells. Any such treatment regimen must be designed in the form of a biological or chemical agent that can be safely used on a patient. Dr. Dwinell and his colleagues in the Department of Biochemistry at the Medical College of Wisconsin are working to design just such a therapy. Because it appears that the absence of CXCL12 in tumor cells contributes to the metastasis of those cells, Dr. Dwinell’s patented approach is focusing on designing a therapy that inserts or places CXCL12 into those cancer cells that specifically lack CXCL12. In other words, Dr. Dwinell hopes to identify specific genes or biological agents that will allow oncologists to craft a targeted therapy that blocks the spread of malignant cancers.
It is important to note that Dr. Dwinell’s work is undertaken with the generous and essential help of the Bobbie Nick Voss Charitable Foundation. This foundation, which has been in existence for many years, provides the economic fuel for much of Dr. Dwinell’s ground-breaking work.
Here is a figure that helps illustrate Dr. Dwinell’s work:
d) The Reality – A Sorry Lack of Funding for this Research.
Unfortunately, despite philanthropic organizations such as the Bobby Nick Voss Charitable Foundation, there is an alarming lack of funding dedicated to the study of metastasis and, thus, the development of drugs that can interfere with the interaction between the first and second proteins needed for metastasis. The hope is that, with sufficient funding and additional time, such a drug will soon be developed that will be tested in clinical trials. If clinical trials show its effectiveness and safety, any such drug may be the proverbial “home run.”
This lack of funding on metastasis and the development of drugs that may stop metastasis will be discussed in a separate post that I anticipate publishing in the next week or two. When one considers both the seriousness of metastatic cancer and the recent breakthroughs on metastasis by Dr. Dwinell and other researchers throughout the world, I believe the limited amount of funding provided for metastatic research will surprise you.
III. A Disclosure and a Personal Comment:
I wish to make sure it is understood that as a patient at the Medical College of Wisconsin Cancer Center and Froedtert Memorial Hospital, I have an affinity for the brilliant and caring doctors and their staffs who have treated me. These doctors and others are identified in the We Thank page of The Triumph Fund’s website, thetriumphfund.org.
Additionally, I have had both the opportunity to tour Dr. Dwinell’s lab and other cancer research labs at the Medical College of Wisconsin. I also have had the privilege and pleasure to discuss their research with these passionate and uncommonly creative individuals. I walk away from such tours and meetings feeling confident that cancer has met its match.
If this post or other posts in this blog suggest that I am impressed with these doctors and scientists at the Medical College of Wisconsin, it is because I am. For that I make no apologies. Instead, I stand and applaud their work and the work of all doctors, scientists, and others, no matter where they are located, who devote their life to the battle against cancer.