There is a very exciting article in the December 8th journal Nature regarding metastasis in cancer that promises to open up new treatment possibilities. Of course MANY cool discoveries never lead to effective treatments, but this could lead to yet another weapon in the arsenal we have to fight cancer. Here is a link to the News and Views article on the new discovery, and here is the actual article.

More below.
To understand cancer treatment, you have to understand cancer. So first I want to give a brief and necessarily over-simplified version of how cancer develops.

Cells are constantly faced with four basic, related decisions: divide, remain quiescent, develop (differentiate) into an effective cell that no longer divides (like nerves, muscle, blood cells, bone, etc.) or die. In general, EACH of these choices, even death, are very carefully regulated in every cell of our bodies and for cancer to develop, defects have to occur in the regulation of EACH of these choices.

For a cell to become cancerous, it first has to become refractory to signals that will either make it differentiate or remain quiescent. That is often one possible mutation. But in normal cells, when they don’t receive proper signals, they are programmed to die. So a cell has to escape this programmed cell death pathway as well. Finally, the cell has to think that it is receiving a signal to divide. So mutations leading to cancer have to occur that do ALL of these things. Some mutations are common in some cancers. For example, the a mutation in the Retinoblastoma gene is one way a cell can escape some of the controls on cell division and this gene is frequently mutated in many cancers, including its eponymous cancer. A mutation that permanently activates one of the Ras genes (a gene that helps to tell a cell to divide) is found in 90% of all pancreatic cancer and 50% of all colon cancer and is overexpressed in some breast cancers. Each gene that is found to be mutated frequently in a type of cancer can suggest a possible treatment. For example, the fact that a type of Ras is so commonly overly active in several cancers has led to the development of a group of drugs (farnasyl trasnferase inhibitors, or FTIs) which inhibit one step in the formation of an active Ras molecule, thus, in theory, interfering with Ras function. Work I did at my former job supported this in many ways and showed why some expected side effects (from the inhibition of certain related genes) don’t happen. It also helped to explain some ways that could be used to prevent cancer cells from escaping from the FTI effect. So a molecular understanding of cancer can lead to possible cancer treatments. Though this is often not as productive as people would like, it has led to some effective treatments like Herceptin, which was discovered almost by accident when studying possible treatments for breast cancers where a particular receptor (Her-2/Neu) is overexpressed. I learned about Herceptin in 1988 and found it sounded wonderful. It was at its earliest trials then and was curing patients who would have died otherwise. It is now becoming part of the standard arsenal of treatments for breast cancer.

The above covers how a cancer STARTS. But it isn’t cancer yet. The now growing ball of cells still needs to find a way to escape the immune system and has to establish a blood supply. It is not well understood how the immune system recognizes and attacks cancer cells, though some work has been done in this area (e.g. my graduate research focused on a group of peptides in white blood cells that could kill both bacteria AND cancer cells). But the need to establish a blood supply was one of the hottest fields of cancer research at the end of the 1990s with the development of angiostatin by Entremed. I just missed investing in Entremed before it boomed, missing a chance to make a small fortune. The day before it skyrocketed, I almost invested. Of course, as is typical of these things, when angiostatin did not prove to be the be-all end-all of cancer cures, people lost interest and the stock plummeted. But the truth is, blocking the development of the blood supply to the tumor WILL be yet another weapon in our arsenal.

That is basically what it takes for a primary tumor to occur–loss of growth controls leading to uncontrolled cell division, evasion of the immune system, and establishment of a blood supply to the growing tumor. Most primary tumors can be removed by surgery or focused radiation treatment, which are still the number one weapons for cancer treatment. Early detection of cancer is critical because if it can be detected early enough, surgery will be adequate to cure the disease, though often they do some chemotherapy or radiation therapy to be sure. Things like Herceptin and angiostatin and FTIs can be used in conjunction with traditional treatments to even further improve outcome.

What do chemo- and radiotherapies do? They are kind of like the blunt club approach to treatment, and their bluntness is why there is so much effort to find new, more specific treatments. Both chemo and radiotherapies do one thing–cause massive amounts of mutations in DNA. These mutations can be repaired in most normal cells, but in rapidly dividing cells there isn’t time to repair the damage and the cell dies. Cancer cells are rapidly dividing cells, but so are our hair, intestinal and immune cells. That is why there are so many side effects from chemo and radiation. The new therapies are simply trying to find things to affect that will MORE SPECIFICALLY kill cancer cells, leaving more normal cells intact. Increased effectiveness and increased specificity are the goals of the new drugs. The difficulty is that cancer cells are derived from normal cells, so the differences can be quite subtle. Hence the fact that so many promising drugs, developed based on molecular understanding of cancer, prove less effective than expected clinically. Another problem is that “cancer” is not one single disease. Each cancer may have its own collection of molecular changes, so many cancers will not be targets of all treatments.

Cancer treatment is so effective today that many cancers are almost completely survivable if caught early. Colon cancer, breast cancer and prostate cancer are extremely treatable if caught early, yet it wasn’t so long ago that they were death sentences. The key, though, is catching them early enough. Why? Metastasis!

The more a cancer develops, the more likely it is that some cells will escape from the primary tumor and find their way to a new location to start a new tumor. This process is called “metastasis” and only the nastiest cancer cells become metastatic. To become metastatic, a cancer cell has to crawl through tissues, enter the blood and glom on to a new location and start to grow again. Metastasis not only means that the doctor now has to look throughout the body for new cancers, but it also means that all those new tumors will be more aggressive and harder to kill and more intertwined with normal tissues than the original tumors. It is usually metastatic tumors that kill us and these are what are called “malignant” because they are the more aggressive cancer cells. Often surgery can’t really deal with a metastatic cancer fully, so very aggressive radiation and/or chemo are needed. Often there is a fine line at this point between killing the cancer and killing the patient. Most of the horror stories of cancer are stories of metastatic cancer. The new therapies are mostly focused on either preventing or better dealing with metastatic cancers.

Which brings me to the new research in Nature. Just like a primary tumor, a metastatic tumor has to surround itself with an amenable niche within the tissues. This includes a blood supply, but also includes other accessory cells that create a friendly environment for the nasty tumor. The primary tumor has the advantage of already being in an amenable environment that it merely has to modify to accommodate a tumor. A metastatic tumor has to create de novo an amenable niche. An early step in this process is the recruitment of cells related to our immune cells (bone marrow derived hematopoeitic cells) that help establish this amenable niche. Up until now, it was assumed that the metastatic cell recruits these hematopoeitic cells once it has arrived at a new location. This has been proven not to be true.

The new study shows that the primary tumor manages to send out signals that recruit the hematopoeitic cells to the site where metastasis occurs BEFORE the metastatic cell leaves the primary tumor. In other words, the tumor recruits normal cells to act as scouts and pioneers to pre-establish a niche that will be ready for colonization by the metastatic cells. From the News and Views:

The capacity of tumours to spread to other organs is one of their most dangerous attributes. A study of how cancer cells settle in new places shows that they send out envoys to prepare the ground for them.

During the process of metastasis, tumour cells move from the primary tumour to colonize another organ. But why do these mobile cells put down roots only in particular organs, or only at specific sites within an organ?…

Metastasis is a sequential process, contingent on tumour cells breaking off from the primary tumour, travelling through the bloodstream, and stopping at a distant site. At the new site, the cells establish a blood supply and can grow to form a life-threatening mass. Both stimulatory and inhibitory molecular pathways within the tumour cell regulate this behaviour4, 5, and interactions between the tumour cell and host cells in the distant site are also significant…

Kaplan et al.3 set up an ingenious experiment to track the movements of various cell populations as tumour cells metastasized in the lungs of live mice (Fig. 1). The mice were irradiated to kill off all their bone-marrow cells, which were then replaced by bone-marrow cells tagged with green fluorescent protein; this made the cells easy to find under a microscope. Once the new bone-marrow cells were established, the mice were injected in the skin with lung carcinoma or melanoma cells, each marked with red fluorescent protein.

The tumour cells were expected to form a primary tumour in the skin, and then to metastasize to the lungs. But the green bone-marrow-derived cells appeared in the lungs on days 12-14 after injection of the red cells — well before any of the tumour cells had arrived in the lung. The red tumour cells turned up only on day 18 post-injection, and by day 23 micrometastases had formed, with more than 95% of the tumour cells being found in exactly the same sites as the bone-marrow-derived cells…

The key is that if either establishment or signaling from the bone-marrow derived hematopoeitic cells was blocked, metastasis was blocked. This is huge! It is not a magic bullet against cancer, and I can tell you that no single magic bullet will ever be found for such a complex disease. But this opens up a whole new avenue of research for potential cancer treatments that may help to reduce the chances of metastasis once cancer is detected. This does not eliminate the need for early detection, but it does mean that the chances of relapse once a body is cleared of tumors can potentially be reduced.

So, what is the politics in here? On the surface, none. But those who know me know that politics is everywhere to me, and the Republican attacks on science are affecting cancer research. All areas of scientific research are being cut year after year. The NIH had been spared much of this until very recently. But budget cuts are hitting the NIH severely now and every professor I know, no matter how well established, is having funding problems. I was laid off from my last job because my boss lost a grant…despite excellent publications. Last year, the NIH was only able to fund 20% of the “desirable” grants, that is, the grants that the NIH would want to fund if it had unlimited money. This year they plan on only funding 10%. And many grants that automatically roll over are no longer being funded 100%, even for top investigators at institutes like Rockefeller. Cancer research is part of this massive cutback. Since my previous boss lost an NIH grant due to these cuts, I am no longer doing cancer research even though much of our work was going very well. How can we develop the next generation of cancer drugs without funding? How can we deal with global warming if global warming research is cut? For those who care about these things, PLEASE contact Congress and tell your Reps to increase science funding and funding for science education. If we don’t do better, we will soon be outsourcing our science. And please help to fight the Republican attacks on science by supporting groups like the Union of Concerned Scientists, the National Center for Science Education and the National Coalition Against Censorship, which has just started a censorship in science project. They didn’t hire me to lead that project (I did interview) but they are still doing good work.

Thanks for the help!

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