Fol. Biol. 2005, 51, 85-88
Milestones in the Field of Tumour Microenvironment Contributions and Perspectives of Professor Isaac P. Witz
As we are now celebrating the 70th birthday of Professor Isaac P. Witz, a leading and pivotal figure in the field of tumour microenvironment, this is an appropriate opportunity to review the milestones in this area, which parallel the scientific career of Professor Witz at the Department of Cell Research and Immunology at Tel Aviv University during the past forty years. Since 1967 Professor Witz has dedicated a major portion of his research career to investigating the "tumour microenvironment". It all began in studies on the role of the immune system in the defence against tumours. The rationale for initiating studies on ""in-situ tumour immunity" was that "there is no reason to assume that expression of immunity is the same in all parts of the body" including the tumour site. Witz et al. showed that various types of in vivo propagating cancer cells in rats, mice and humans are coated with an "immunoglobulin (Ig) coat". This coat consisted of a mixture of tumourreactive antibodies, undetectable in the circulation, and of unrelated immune complexes. In addition, immunoglobulins which totally lacked specificity to the tumour cells, and antibodies directed against membrane antigens expressed on normal and on tumour cells were detected. These findings led to a detailed study of the expression of Fc-receptors (FcR) on tumour cells. Such receptors were indeed detected on certain in vivo growing mouse tumours. Moreover, it could be shown later that the expression of FcR in FcR-positive cells was induced by microenvironmental factors such as INFγ. Surprisingly, transfection of FcγRII cDNA into FcRnegative tumour cells enhanced the tumorigenicity of the transfectants. Importantly, expression of FcR by tumour cells was lost and their tumorigenicity was attenuated following their adoption into culture. These experiments led to the conclusion that FcR exerted tumour-enhancing activity by delivering "malignancyenhancing signals" to the tumour cells. Further studies conducted by Professor Witz and others established the role and implications of FcR tumorigenicity. Another set of studies was aimed at exploring the mutual interactions between tumour cells and microenvironment. For instance, it was shown that tumour-derived proteolytic enzymes were able to degrade Ig molecules in their microenvironment. This activity eliminated Fcmediated functions of the antibodies such as complement-dependent cytotoxicity, and generated "blocking" Fab fragments that actually protected tumour cells from cytotoxic activity.
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