Biopeer

In their recent paper entitled Systemic Endocrine Instigation of Indolent Tumor Growth Required Osteopontin (published in Cell 133, 994-1005, June 13, 2008), McAllister and co-workers from Robert Weinberg’s lab at Whitehead Institute propose the following fascinating model (see Figure 7D). Aggressive primary tumor cells secrete an endocrine factor called Osteopontin. In turn, Osteopontin then activates a population of hematopoietic cells in the bone marrow. These activated bone marrow cells are subsequently recruited to stroma of distant tumors, and enhance the outgrowth of once indolent (i.e. slow-growing) tumors into aggressive adenocarcinomas.

I would like to call this model a “predestination model”. On one hand, it offers a grim scenario for a patient, while at the same time it may provide a hope for new cures. Suppose a person has an aggressive breast tumor (incidentally, the paper uses the cell lines derived breast cancer). What this model is saying is that even when this tumor is surgically removed, the bone marrow cells of the patient have already been reprogrammed or “activated” by this aggressive tumor. Then these bone marrow cells will travel to distant sites, where there are either indolent metastatic cells derived from the primary tumor or potentially, other unrelated independently-derived tumors (e.g. colon polyps), and by integrating into the stroma (the environment) of these indolent tumors, make them into aggressive adenocarcinomas. Hence the name “predestination”, the patient is bound to get the aggressive form of cancer because he or she has the "pre-programmed” activated bone marrow population.

Let us look into the elegant design of the system that the researchers utilized in their paper. Their system is based on the technique of bi-lateral injection of nude (immunocompromised) mice. In their system, McAllister et.al used two types of cell lines. One is called an “instigator”, it is an aggressive, fast-growing human breast cancer cell line. The other is called a “responder” cell line, as it a transformed mammary epithelial cell line, but it can only induce tumors in only 25% of mice injected with these “indolent” (slow growing) cells. They inject one flank of a host mouse with the instigator, and the other flank with the responder, as a control, they also inject host mice with a matrigel control vehicle (instead of the instigator cells), and on the other flank with the responders. Their initial intriguing finding is that the instigators enhance the tumor forming ability of the responders, whereas in the controls, there is no visible tumor growth. This indicated that the instigators somehow changed the tumor forming stromal environment of the responders.

Since it has been shown previously that certain types of stroma consists of recruited bone marrow cells, the researchers were motivated to examine whether the instigators recruited the bone marrow cells. In another clever experiment, they replaced the bone marrow of nude mice with the bone marrow, which was GFP positive. Following that they found that GFP positive cells were incorporated into the stroma of “responder” tumors.

One particularly interesting finding is that the specific population of bone marrow that was preferentially recruited to these responder tumors was characterized as Sca1⁺/cKit^-as determined by antibody staining and flow cytometry. As the authors write in their discussion section, this population of bone marrow cells is known as “mystery population”, their purpose is currently unknown. Targetting this population of cells may provide new therapy solutions for preventing metastasis, such as for instance creating an antibody based therapy that would tag this particular population of bone marrow cells for destruction, and thus prevent them from traveling to secondary tumor sites.

-Maria Lazebnik, Ph.D.

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