Can engineered bacteria help control cancer?

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Abstract
Hypoxia and anoxia are pathophysiologic characteristics of most solid tumors (1, 2). For nearly 150 years, nonpathogenic, anaerobic bacteria that preferentially localize and proliferate in the hypoxic regions of tumors have been investigated as treatments for experimental and human tumors with mixed success (Table 1). In recent years, there has been a renewed interest in using these bacteria as innovative delivery vehicles for gene therapy (Table 1). Now, as described in this issue of PNAS, Vogelstein and coworkers (11) have created a new strain of anaerobic bacteria, devoid of its toxic genes, that leads to dramatic and prolonged regression of subcutaneous tumors when systematically administered with conventional drugs. This strategy, referred to as combination bacteriolytic therapy (COBALT), adds a new weapon in the war against cancer. However, there are still obstacles that need to be overcome before it can be used safely in the clinic. Ironically, a tumor's metabolically compromised microenvironment provides a haven for a number of anaerobic bacteria. Examples of bacteriolytic therapy of tumors in vivo In tumors, blood vessels are structurally and functionally abnormal, resulting in temporally and spatially heterogeneous blood flow (19, 20). This heterogeneity hinders the delivery of blood-borne therapeutics to all cancer cells and leads to acutely and/or chronically hypoxic and acidic regions in tumors (Fig. 1). These conditions reduce the effectiveness of radiation and some chemotherapeutic agents and select for cancer cells that are more aggressive, metastatic, and resistant to various therapies (2, 21). Schematic of three microenvironmental regions in a centrally necrotic tumor. A spontaneous tumor may consist of many such necrotic foci. Decreasing magnitude of various physiological parameters is indicated as +++, ++, +, +/−, and −. Ironically, a tumor's metabolically …