Metastasis Awakening: Targeting dormant cancer

An important challenge for oncologists is to treat overt metastasis, the major source of cancer-related deaths1. Adjuvant therapy should prevent distant recurrences by targeting residual disseminated tumor cells (DTCs) that give origin to metastasis, as well as existing undetected micrometastasis. Whereas in some cases, such as breast cancer, patients can show delayed metastasis after hormonal therapies (for example, in estrogen receptor–positive tumors) or treatment with trastuzumab, for HER2 (also called ERBB2)-positive tumors2, adjuvant therapy is for the most part ineffective in fully blocking metastasis development and improving overall survival. This may be explained by the fact that the biology of residual DTCs seems to diverge from that of the primary tumors and overt metastasis3. The usually unpredictable timing of metastasis can be due to the ability of DTCs to enter dormancy1. Dormant DTCs can in turn be refractory to targeted or conventional therapies2, further limiting treatment responses. Notably, more than 67% of deaths in patients with breast cancer occur after the 5-year survival mark, showing that residual disease can be dormant for very long periods1. This further argues that targeting dormant DTCs is crucial. Unfortunately, compared to other areas of cancer, our understanding of the biology of dormant residual DTCs is highly limited. Thus, ‘bedside’ clinical management of dormant disease will be a reality only after rigorous understanding of its molecular and cellular basis. There is compelling evidence that the presence of DTCs in the bone marrow of patients with breast or other cancers is a poor prognosis indicator1. However, although some DTC-positive patients recur 3 years after surgery, others do so up to a decade later1. Characterization of DTCs from patients may be the shortest path to determine which and when patients might relapse and identify DTC-specific mechanisms to target. A study in esophageal cancer showed that direct genetic analysis of DTCs predicted outcome and therapy selection3. An amplification of the region harboring HER2 was found in the primary tumors and DTCs; however, the HER2 amplification was only predictive of poor patient survival when detected in disseminated tumor cells. Notably, esophageal tumor cell lines with HER2 amplification were sensitive to commonly used therapies designed for breast cancer (for example, trastuzumab)3. DTCs in the bone marrow of patients are largely nonproliferative2 and DTCs—but not circulating tumor cells—can persist in the target organs for long periods (up to a decade)1, suggesting that DTCs probably enter cellular dormancy through quiescence2. Although eradicating dormant DTCs or keeping them dormant could be a new strategy to prevent metastasis2, achievement of such a goal in the clinic requires answering at least two important questions. First, can DTCs serve as a biomarker when typified during recurrence or dormancy? And second, can we identify dormant DTC– specific or microenvironment-dependent mechanisms that could be manipulated to maintain or eradicate dormant disease? Microenvironmental signals that cause a low-mitogenic and high-stress signaling and trigger quiescence may constitute dormancy mechanisms2,4,5. For instance, blockade of the urokinase receptor (uPAR) inhibits fibronectin-dependent mitogenic signaling by reducing the activation of a5b1 integrin and epidermal growth factor receptor (EGFR)2, resulting in extracellular signal–related kinase (ERK) deactivation and subsequent p38 activation, which further antagonizes ERK to induce quiescence2,4. Interestingly, uPARlow/– DTCs in the bone marrow of patients with gastric carcinoma ■ BenCh To BeDSIDe