Seeds and Soil: Unraveling the Role of Local Tumor Stroma in Distant Metastasis

Distant metastasis is the chief cause of cancer mortality. This is particularly true for breast cancer, for which the last decades have brought notable advances in locoregional (surgical, radiation) and systemic (hormonal, chemotherapies) treatment approaches. However, metastatic progression remains a poorly understood process. Therefore, it has been difficult to predict the presence of occult micrometastases in patients and the molecular and cellular mechanisms critical for their formation and progression. As a result, devising novel anti-metastatic therapies has been and remains a great challenge in oncology. Certain gene signatures (eg, MammaPrint, Oncotype DX) have shown statistically significant association with distant disease recurrence and are in clinical use as prognostic markers. These signatures appear to be driven predominately by genes reflecting the level of proliferation and hormone receptors in those tumors. But in addition to intrinsic properties of the cancer cells, a key role has been proposed for the tumor microenvironment in cancer cell survival and progression to metastasis. The contribution of the microenvironment may enhance an otherwise very inefficient process (1,2) and includes angiogenesis and the multi-faceted participation of activated fibroblasts and immune cells. Our understanding of this process is largely based on evidence from mouse models. However, the murine models have several limitations and may not fully reproduce the metastatic cascade in patients. Most metastasis studies have utilized experimental models in which cancer cells are injected as a bolus into the circulation upstream of the metastatic site. The limitation of such an approach is that it overlooks critical events taking place in the primary tumor and systemically prior to metastatic cell colonization. Models featuring spontaneous metastasis from a primary tumor are markedly better; however, these models generally do not metastasize to the same site(s) as the human disease they aim to model. Furthermore, such models are rare, and their metastatic cascade phenomena may represent only a small subset of possible human cases. Both implanted cancer cell models and genetically engineered mouse models—the current gold standard for understanding cancer biology—have these limitations. Finally, although most new agents are first tested in the metastatic setting, more recently there has been considerable interest in evaluating novel therapeutic agents in the neoadjuvant (preoperative) setting for some aggressive subtypes of breast cancer (eg, triple-negative and human epidermal growth factor receptor 2 [HER2]-positive). This approach offers the potential for accelerated Food and Drug Administration approval if the agent demonstrates a substantial increase in the rate of pathological complete response of the primary cancer (3). However, therapeutic effects on the primary cancer may not accurately reflect effects on micrometastatic disease in the setting of a different microenvironment. Preclinical studies often provide little insight in this regard, because most of them are done in primary tumors with no metastasis. This discordance may help explain the observation that drugs that increase pathological complete response rates have failed to decrease rates of metastatic disease. In a report in this issue of the Journal, Rohan et al. examined whether the frequency of microstructural units formed by cancer cells, perivascular macrophages and endothelial cells— termed Tumor MicroEnvironment for Metastasis or TMEM— are associated with the risk of metastatic recurrence (4). The authors identified the cancer cells that comigrate and interact with macrophages at intravasation sites based on the expression of Mena, which is an Ena/VASP protein family member and a