Cancers become most deadly when they metastasize, yet finding ways to combat metastasis has been a significant Achilles heel of cancer research. But our growing understanding of the role that a tumor's "microenvironment" plays in metastasis may allow us to shift the tide.

We now know that the tumor microenvironment is an important component of tumor initiation, progression, and metastasis, and as a result, may play prominently in the development of new therapeutic approaches to combating cancer. The tumor microenvironment, or stroma, not only contributes to some of the destructive characteristics of malignant cells, but it also can undermine treatment by partially shielding tumors from therapeutics, altering drug metabolism, and contributing to drug resistance. Because stromal elements figure in all stages of tumor development, they represent attractive therapeutic targets. Manipulating host-tumor interactions, for example, may help prevent cells from becoming malignant or even encourage malignant cells to revert to their normal state.

Despite the importance of interactions between the tumor and stroma, we have a limited understanding of the components that compose the stroma and the stroma and tumor's complex relationship. We know generally that tumor stroma consists of cells (such as fibroblasts, epithelial cells, and inflammatory cells), extracellular matrix, and extracellular molecules. We do not know, however, the precise nature of the cells that compose normal stroma, how these cells or newly recruited cells are altered during tumor progression, and how they influence tumor initiation and progression.

By addressing these questions, we can begin to develop therapeutic strategies that target both the microenvironment and the tumor. This will likely include the development of drugs that induce apoptosis, inhibit stromal cell function, or inhibit the factors secreted by stromal cells that are required for tumor progression and metastasis. As our understanding of the tumor microenvironment grows, we also believe it will lead to the development of new diagnostic and prognostic tests. Finally, it may be possible to develop strategies to prevent the development of tumors based on our understanding of the microenvironment changes required for tumor development.

NCI is committed to promoting research aimed at better understanding the tumor microenvironment and its interaction with the tumor, and identifying and characterizing the molecular "signatures" of seemingly normal cells within the tumor microenvironment as well as signatures that reflect changes that occur as cancer cells interact with the host microenvironment.

The formation of interdisciplinary research teams and multi-institutional collaborations is critical to expediting our achievement of this goal, and NCI is beginning to explore how best to facilitate these activities. Similarly, the development of enabling technologies will be critical to advances in this field. A number of technologies have been identified as critical to this effort, including novel in vitro 3-D organotypic models and animal models; techniques for the isolation and characterization of stromal cells, such as laser capture microscopy; and the development of reagents that can be used in in vivo imaging to visualize tumor-host interactions based on stromal markers identified through molecular profiling.

The combination of collaboration and enabling technologies has set the stage for significant advances in this area, especially the development of tissue- or cell-specific targeting agents. During the coming year, we will actively pursue approaches to respond effectively to both of these needs. In the end, we would like to make the microenvironment around tumors a hostile host, disrupting or averting metastasis. At its most effective, this approach, in combination with other therapies, may very well help to transform cancer into a chronic but benign disease - one with which patients can lead long and productive lives.

Dr. Dinah Singer
Director, Division of Cancer Biology

Dr. Suresh Mohla
Chief, Tumor Biology and
Metastasis Branch