BBB & CCBIO seminar: Zena Werb
New insights into mechanisms underlying breast cancer metastasis
Department of Anatomy, and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA
The major cause of cancer-associated mortality is metastasis, but our understanding of this process is far from complete. Tumor cells invade the surrounding tissue of the primary tumor, intravasate into blood and lymphatic vessels, survive and translocate to distant tissues, extravasate, adapt to the new microenvironment and eventually seed, proliferate and colonize to form metastases. Over 125 years ago, Paget enunciated the seed and soil hypothesis of cancer. More recently, emerging data suggested that the cellular and extracellular matrix (ECM) microenvironments – both in the primary tumor and in metastatic sites – are crucial at multiple stages of metastasis. Significantly, targeting the tumor microenvironment in metastasis might hold promise for therapy as stromal cells are not mutated and the effects may be widespread as the ECM interacts with multiple tumor cells. The ECM is a rich reservoir of pro- and anti-angiogenic cues that regulates neovascularization of the tumor, a crucial process in tumor cell dissemination. The developing metastatic lesions result from a complex crosstalk between disseminating tumor cells and the different players in the microenvironment of the metastatic lesion. The specific recruitment of distinct populations of leukocytes and stromal cells with overlapping functions in metastasis may open new avenues to the development of metastasis-targeted therapies. Finally, the function of the tumor microenvironment in modulating sensitivity to chemotherapy is of clinical importance. But the aspects of how the microenvironment contributes to loss of drug efficacy are still poorly understood in the metastatic setting. The microenvironment is an important source of anticancer drug resistance and also a therapeutic target, as drugs might not need to be completely penetrant to be effective because altering some immune cells, ECM components or the vasculature may have profound effects as seen with regulation of microRNAs. The microenvironment faced by cells at metastatic sites also determines whether these cells die, proliferate or become dormant. How does the microenvironment evolve from the pre-metastatic stage to established metastases? Determining whether the metastatic niche arises from changes in the ECM, decreased immune surveillance or changes in specific pro-inflammatory molecules poses a challenge for the future. We need a more complete understanding of the role of the metastatic microenvironment to uncover how these processes promote metastasis.
Chairperson: Marion Kusche-Gullberg, Department of Biomedicine