Publications

Understanding the pathomechanism of cancer is of primary interest ín medi­cal research (Trosko and Rauch, 1998; Bjerkvig et al., 2005). ln the past century, several mechanisms were proposed. It was hypothesized that cancer arises from a single cell that loses its differentiated state through sequential mutations. This initiation-promotion-progression concept explains the steps in a sequential process. Later, this hypothesis led to the muta­genic and recently the oncogenic theories, which hypothesize that defects in tumor suppressor genes are responsible for the development of cancer. The impairment of cell-to-cell communication as a cause of cancer has also been postulated.

Environmental effects, such as chemical carcinogens or life style factors, such as alcohol or tobacco consumption or drug abuse, could also cause mutations and other genetic abnormalities observed ín cancer cells. The discovery of the cancer stem cell lent support to the theory that cancer rp_ay develop from a single cell, and raised the question of cancer stem cells arising from normal stem cells. lndeed, if normal stem cells could undergo the type of mutations· observed in tumor cells, this would potentially compromise the genetíc stability of the organism. Therefore, the likelihood that normal stem cells are very well protected is demonstrated by their resistance to radiation and toxins (Dean et al., 2005).

One fascinating finding is that immuno­ suppressive cytotoxic antineoplastic thera­ pies may, on occasion, cause the regression of a clinically established cancer. At first, applying this as a therapeutic strategy may seem counterintuitive, considering the fundamental role of the, immune system ín protecting the body against infectious organisms and abertant cells. ln addition, cancer itself is frequently immunosup­ pressive, so exacerbating a pre-existing immunosuppression may not seem like a rational strategy.

ln this light, it appears paradoxical that the same degree of immunosuppression that is lethal in a bacterial or fungal infection actually benefits cancer suppression. ln other words, the deletion of the T cell compartment that accompanies cytotox1c antineoplastic therapies may facilitate cancer regression (Mackall, 2000). This suggests that cancer itself may arise from the immune system, potentially from the T cell compartment, which would explain why the suppression of cellular immu­nity could also lead to the suppression of the disease. Another observation is that tumor cells are poorly immunogenic, despite the fact that tumor cells are anti­ genic. Therefore, they do not generate a T cell-mediated immune response, and if so, it is of low intensity (Melief, 2000). lf tumor cells were derived from injured lymphocytes, particularly T cells that still share some functional properties with their normal counterparts, an immune toler­ance to cancer cells could be explained, as the immune system is not made to attack itself. ln pathological situations, T cells do attack self-tissue in a manner reminiscent of the autoreactive nature of cancer cells, which have the ability to attack and invade host tissues. ln other words, cancer cells behave like autoreactive lymphocytes. Here, we explore the evidence suggesting that such a mechanism could be at work during cancer development.

The prevalent genetic theories of cancer are built upon observations of genetic abnormalities in tumor cells. These theo­ries do not generally take into account the demonstrated importance of environmen­tal factors in human cancer development. ln a previous article, Grandics (2003) has shown that specific dietary deficien­ cies mimic the effects of chemical or radiation damage to DNA, which we propose plays an important role in human carcinogenesis and tumorigenesis. This observation allows us to consider cancer as a single disease, possibly developing from a single cancer stem cell. Based on this observation, we could assume that the observed genomic abnormalities in cancer cells are an effect rather than the cause of the disease. This idea also points to the direction of upstream events preceding the development of the malignant cell. We propose that identifying these events will be fundamental to understanding the pathomechanism of cancer. By explor­ ing the functional similarities between lymphocytes and cancer cells, we provide an insight into this realm of possible upstream events.