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Institute of Environmental Medicine, Division of Toxicology, Karolinska Institutet, Stockholm, Sweden; and
* NUS Graduate School of Integrative Sciences and Engineering, and Department of Physiology, Faculty of Medicine, National University of Singapore, Singapore
1Correspondence: NUS Graduate School of Integrative Sciences and Engineering, Department of Physiology, Faculty of Medicine, National University of Singapore, MD9 #03-06, Singapore. E-mail: phssp{at}nus.edu.sg
ABSTRACT
The heightened interest in the development of novel anti-cancer drugs that trigger apoptotic death in cancer cells stems from the fact that immediately upon execution of the death signal, the corpse is efficiently removed via specific recruitment of phagocytic cells. This prevents spilling of cellular contents and the associated inflammatory response, a likely scenario during necrotic death. Recent evidence has established that phagocytic removal of apoptotic cells is a function of ligand–receptor interaction, whereby the ligand(s) for the scavenger receptor(s) of phagocytic cells is/are specifically expressed on apoptosing cells. Therefore, by implication, enhancing this ligand–receptor interaction could be an alternate means for removing unwanted cells. Here we present a provocative hypothesis that circumvents the need for chemotherapy-induced apoptosis in cancer cells. According to our model, cancer cells need not die in order to be removed by scavenger cells, but could still be effectively phagocytosed provided the cell surface expression of specific molecules that strongly engage phagocytic cells is sufficiently enhanced. In other words, inducing the expression of "eat me" signals on cancer cells could be a novel approach to "bury alive" these unwanted cells without the untoward effects of chemotherapy-induced apoptosis.—Fadeel, B., Orrenius, S., Pervaiz, S. Buried alive: a novel approach to cancer treatment.
Key Words: cancer cells • apoptosis • scavenger receptors • phagocytosis • cell clearance
MOST, IF NOT ALL, chemotherapeutic agents kill cancer cells through the induction of apoptosis (1
2
3
). This highly conserved mode of cell death involves activation of cysteine-dependent proteases, termed caspases, and amplification of the proteolytic cascade through the release of proapoptotic factors from mitochondria, and culminates in the swift clearance of dying cells by neighboring phagocytes (4)
. Notwithstanding the tremendous strides over the last decades in our understanding of the effector mechanism(s) involved in cellular commitment to and execution of apoptosis, the molecular events that govern the recognition and engulfment of effete cells remain poorly understood. Nevertheless, studies in recent years have disclosed that cells undergoing apoptosis express specific "eat me" signals, including lipids (most notably, phosphatidylserine, or PS), proteins (annexin I), and modified sugar moieties, that facilitate recognition and ingestion by macrophages (5)
. The phagocytic cell in turn has been shown to employ an array of receptors (scavenger receptors, integrin receptors, the so-called PS receptor, and others) that mediate efficient disposal of effete cells (4
, 5)
. In addition, soluble bridging molecules such as thrombospondin and milk fat globule epidermal growth factor-8 (MFG-E8) can facilitate the engulfment process (5)
. It has been speculated that dying cells emit chemotactic signals in order to selectively recruit more phagocytes to the site of cell attrition; recent studies have identified the phospholipid lysophosphatidylcholine as a candidate for mediating the attraction of macrophages to apoptotic cells (6)
. Taken together, these specific interactions ensure that inflammation and tissue scarring due to secondary necrosis of "neglected" apoptotic cells are limited. Given the realization that most current drug therapies trigger apoptosis of cancer cells and the fact that the efficient recognition of apoptotic cells by professional phagocytes is a crucial feature of the apoptotic process, we present here a provocative hypothesis that enforced phagocytosis in the absence of a death signal may serve as an efficient means of deleting cancer cells without the associated bystander effects observed during conventional chemotherapeutic treatment. In other words, we suggest that cancer cells may be "buried alive" upon exposition of appropriate macrophage recognition signals.
Phagocytic recognition of cells destined for destruction is a process that is conserved from nematodes to mammals (5)
. Recent studies in various models have shown that the engulfment of apoptotic debris is not merely a matter of waste disposal, but rather an active process with numerous immunological consequences (7)
. Hence, macrophage engulfment of apoptotic, but not necrotic, cells results in the secretion of cytokines that serve to down-regulate deleterious inflammatory responses (4)
. Moreover, studies in Caenorhabditis elegans have indicated that the engulfment process can promote the execution of the cell destined to die (8
, 9)
. These observations bear witness to the fact that during the terminal stages of apoptosis, phagocytes do not function solely as "undertakers," but also ensure the orderly execution of the death process in the dying cell. Consequently, perturbation of the process of clearance of cells undergoing apoptosis could have deleterious consequences. Hence, in the absence of phagocytosis, apoptotic cells are thought to undergo secondary necrosis with release of large quantities of degradative enzymes, resulting in tissue damage and inflammation (4)
. The contents of cells dying by apoptosis also have the potential to induce undesirable immune responses (7)
. First, the caspase-driven dismantling of cells may be potentially harmful, as this may generate neoantigens that become accessible on the surface of apoptotic cells, thus yielding autoimmune responses (10
, 11)
. Second, apoptotic cell debris may function as an immunogen to stimulate the production of autoantibodies (12)
. Moreover, recent studies have demonstrated that horizontal transfer of oncogenes through engulfment of apoptotic bodies may transpire within a tumor cell population, providing a mechanism for the propagation of genetic instability and/or diversity in tumors (13)
. These data present reasonable grounds to suggest that the clearance of apoptotic cells is not an infallible mechanism and that inefficient recognition signals and/or defective phagocytic responses could sometimes be harmful.
DO CANCER CELLS HAVE TO DIE TO BE ENGULFED?
Schroit and colleagues have shown that red blood cells containing an exogenous PS analog in their plasma membrane are rapidly cleared from the peripheral circulation of syngeneic mice (14)
, suggesting that viable cells can be engulfed if they express appropriate eat me signals. Given the critical role of clearance of cell corpses in the terminal stages of apoptosis, a provocative hypothesis would be to test whether the deletion of cancer cells could be accomplished in the absence of a death signal. Enhancing the expression of eat me signals on the surface of cancer cells or their reciprocal receptors on phagocytic cells thus might constitute an alternative to chemotherapeutic ablation of tumors (Fig. 1
). Attention should of course focus on the issue of tumor specificity of this putative approach. However, recent in vitro studies provide impetus to our hypothesis. We have demonstrated that treatment of the B lymphoma cell line Raji, which fails to externalize PS upon death receptor (Fas/APO-1/CD95)- or etoposide-induced apoptosis, with N-ethylmaleimide not only triggered PS exposure, but also resulted in the efficient engulfment of these cells by macrophages despite the absence of other indices of apoptosis, such as caspase activation and nuclear fragmentation (15)
. Furthermore, we could show that enrichment of the plasma membrane of nonapoptotic tumor cells of lymphoid (Raji, Jurkat) and myeloid (HL-60) origin, respectively, with exogenous PS and/or oxidized PS (PS-OX) suffices to render these cells appetizing to macrophage (15)
. It was recently shown that nonapoptotic neutrophils express repulsive signals that prevent ingestion by macrophages and that such signals need to be "disabled" in apoptotic cells for phagocytosis to occur (16)
. Our findings, however, argue against a general requirement for disabled detachment in cell clearance insofar as the exposure of PS and/or PS-OX was sufficient to trigger engulfment of viable tumor cells. Transfection of the scavenger receptor CD36 into human melanoma cells was reported to confer an increased capacity to ingest apoptotic cells comparable to those exhibited by "professional" phagocytes (i.e., macrophages) (17)
. In a similar experiment, gene transfer of the PS receptor into B and T lymphocytes enabled these otherwise nonphagocytic cells to recognize and efficiently engulf apoptotic cells (18)
. Taken together, these data support our hypothesis that the expression of recognition signals (such as PS and/or PS-OX) on target cells as well as the expression of their cognate receptors on phagocytic cells (amateur or professional) could enhance clearance of "un-dead" cancer cells. Indeed, one could take this a step further and propose a model whereby the concomitant induction of phagocytic receptors and eat me flags in cancer cells might result in self-engulfment of the tumor, i.e., cancer clearance by the cancer itself. This would be a challenging model to test, but could have tremendous potential as a therapeutic tool to accomplish "burial" of live cancer cells without the need for conventional chemotherapeutic drugs.
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Received for publication June 23, 2003. Accepted for publication September 16, 2003.
REFERENCES
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