Cancer Cellular Ecology

This post kicks off my contribution to Just Science 2007. While it won't be a theme held to strictly, many of my planned entries will be about, or touch on, cancer.

Carl Zimmer had an excellent recent post on the evolutionary aspects of cancer; here I will take a stab at the cellular ecology of cancer. It is both a fascinating topic on its own, and something which later posts this week will refer back to. For this last reason, this post will also be sprinkled with teaser references to posts which will show up later in the week.

I don't remember when I first heard about cancer, but it was at a tender age. I don't remember the context either. My paternal grandmother succumbed to leukemia long before my parents met, at a time when leukemia was considered incurable -- though within a few years the first effect chemotherapeutic agents would appear. Or perhaps it was hearing about the boy a street over who died of childhood leukemia. Most certainly I knew by 2nd grade, as that is when the kindly custodian at my elementary school died of cancer. So sometime I heard the word, and I was not one to withhold questions.

The answer I got that first time, and for many times later, is that cancer is part of the body gone haywire, an uncontrolled & chaotic growth that eventually crowds out normal tissue. One analogy is that of a weed which takes over the garden. It's a very simple answer -- suitable for an inquisitive elementary school student -- and it's also the model that long held sway. But the modern view is much more complex. That complexity extends the mystery of cancer, but also offers new opportunities for treating it.

First off, the modern view is of a tumor with some internal complexity; we now believe that many, and perhaps all, malignant tumors have at least two classes of cells: cancer stem cells (more later this week) and the bulk of the tumor. But furthermore, the tumor recruits other cells to assist it. Depending on the tumor type, these could include endothelial cells to build new blood vessels (a process called angiogenesis), fibroblasts which become the tumor stroma, and immune cells which may be co-opted to provide useful signals to the tumor. There's a fascinating story of the intersection of tumor, endothelial cells & stroma that will follow later. Other interactions may depend on the tumor type.

For example, take the interaction of multiple myeloma & the bone marrow. Normal bone marrow contains a host of different cell types & interacts with the nearby bone. Normal bone is maintained by a healthy balance between two opposed cellular factions: osteoclasts which break bone and osteoblasts which build bone. Both are derived from Greek, with osteoclast being my favorite because of it's onomatopoetic root 'clastos' (to break).

Multiple myeloma results from the derangement of a plasma cell, the final stage in B-cell development (free review). B-cells are the antibody producing cells, and go through a complex series of transformations. A unifying theory of B-cell malignancies (B-cell leukemias, B-cell lymphomas & multiple myleoma) is that each represents a cell leaving the tracks at a certain stage of B-cell development. Myeloma represents the derangement of the final stage, a plasma cell, whose normal job is to secrete large quantities of a single antibody. One of the clinical hallmarks of multiple myeloma is the overabundance of a single antibody species in the blood. An even more devastating effect is bone destruction; on some of the X-rays the patient's skullcase literally looked like swiss cheese.

This clinical sign has a relatively straightforward cellular explanation: Myeloma cells stimulate the numbers of osteoclasts. This benefits the myeloma cells via osteoclasts secreting various growth factors favorable to myeloma cells. Myeloma cells reciprocate both by stimulating mature osteoclasts and by encouraging the common progenitor of osteoclasts and osteoblasts to more often mature into osteoclasts. Myelomas may also send hostile signals to osteoblasts, encouraging them to commit suicide. A new garden metaphor appears: myelomas cultivate their surroundings & fertilize their soil.

Many of the active drugs for myeloma, including my former employer's drug Velcade, may work by both targeting the myeloma cells but also targeting these interactions with their cellular microenvironment. If a drug can block the stimulation of osteoclasts, or attenuate the inhibition of osteoblasts, then useful clinical benefits might ensue -- such as reduced bone damage but also perhaps dampening the stimulatory signals from the osteoclasts to the myeloma cells.

Many existing drugs may target other cellular ecological interactions in tumors. In particular, many drugs may antagonize angiogenesis, the formation of new blood vessels to feed the tumor. The first drug targeting angiogenesis specifically, Avastin, appeared about two years ago, and more will undoubtedly appear.

An important implication of this sort of thinking is questioning the very way we study cancer. Much early stage research is based on tumor cell lines in culture -- cell lines which do not have any cellular partners present. Mouse models using human cell lines may not recapitulate these cellular interactions, as the mouse and human cells may be communicating inefficiently due to different molecular accents. Even looking at humans, pharmacogenomics studies which extract signal only from tumor may be missing much of the picture. In addition, most cancer models and many early stage cancer clinical trials are based on reductions in the size of the tumor as the figure-of-merit. Therapies targeting the cellular ecology might not produce rapid, drastic changes in tumor volume. New models must be (and have been) developed & validated, and they are often more complex and take longer or more resources to execute. Complexity breeds complexity -- and we have no idea how many more complexities we will encounter.

But in the end, we have no choice. We can try to make simple models of what cancer is, but if you are trying to treat a complex disease you need an appropriately complex model. But if you're trying to explain cancer to a second grader, perhaps you need to fall back on the 'cancer is like a weed' explanation.

[Note: Blogger has an odd way of timestamping posts you save as drafts, so I'm adding this note to try to get this popped into the Week of Science]
[updating again to try to push this through]