Sinister Self-Sacrifice: The Contribution of Apoptosis to Malignancy

Induction of apoptosis is one of the main defenses of the body against cells that have acquired malicious mutations. It may seem counter-intuitive then, that massive cell death is observed in many malignant tumors (1, 2). Despite high rates of apoptosis, these tumors continue to grow rapidly. Thus, tumor cell growth must outbalance tumor cell death. Intuitively presumed only to inhibit tumor growth, apoptotic cells may actually promote net tumor growth (3, 4). As long ago as 1956, Revesz showed that cell death can enhance tumor growth (5). Moreover, new studies in progress in our laboratory show that apoptosis in tumor cells promotes growth rates in aggressive B-cell lymphoma. Cells undergoing apoptosis are difficult to observe in vivo, as they are rapidly cleared by phagocytosis, most obviously by macrophages. Accumulation of macrophages, sometimes engorged with apoptotic cells, is observed in many malignant tumors and is generally associated with poor prognosis (6, 7). Inflammatory cells, in particular macrophages, are key elements of the tumor environment, providing support for the continually expanding “rogue” tissue. The tumor microenvironment resembles that of a wound that fails to heal (8), where macrophages not only clear and repair, but also promote tissue regeneration and support. Tumor-associated macrophages (TAM) display a phenotype that is reminiscent of wound-healing macrophages. They have been shown to promote angiogenesis, tissue remodeling, and anti-inflammatory responses, which results in the support of tumor cell growth and metastasis (9–12). Apoptosis of tumor cells in a growing malignant tissue may therefore be rationalized as a “sinister sacrifice” of some cancer cells that ultimately facilitates cancer progression. We hypothesize that apoptotic cells play a key role in driving oncogenesis, both through the release of soluble and microvesicle-associated signaling factors, as well as through direct interaction with phagocytes. Here we postulate lactoferrin (Lf) as an important signaling factor maintaining an antiinflammatory tumor microenvironment, and stress the importance of apoptotic cell engulfment by macrophages for driving a pro-tumor phenotype in TAM (Figure 1).