MERIT Award Recipient: Avraham Raz, Ph.D.
The Role of Tumor Cell Surface Lectin in Metastases
Metastasis, the epitome of cancer progression, is a pathological process of profound significance, because much of cancer's lethality is from malignant neoplasms and thus any experimental attempt aimed at better understanding this process should be encouraged. Dr. Raz's saga in this field of research started in 1980 when as a Postdoctoral Fellow he published, in Nature, one of the first observations linking an in vitro phenomenon to in vivo metastasis showing the propensity of cancer cells to undergo homotypic aggregation. This inaugurated the role of galectins in cancer by raising the question "What mediates cell-cell adhesion?" A detailed analysis revealed that cell-cell recognition is mediated by carbohydrate recognition, that simple sugars containing galactose residues can block the reaction, and that tumor cells express a galactose-specific lectin(s). At that time, sugar-binding proteins (lectins) were thought to belong only or mainly to the plant kingdom and it was unheard of that mammalian cells in general and cancer cells in particular express lectin(s). Due to this initial skepticism, Cancer Research agreed to publish the work only after the word 'like' was added to the Title: "Lectin-like activities associated with human and murine neoplastic cells". He was the first to identify, clone and generate monoclonal antibodies against tumor lectins. The field grew and was legitimized in 1994 when he published in Cell "Galectins: a family of animal-beta-galactoside-binding lectins" Galectins are animal lectins that bind Β- galactosides through evolutionarily conserved sequence elements of the carbohydrate recognition-binding domain. To date 14 members of the galectin family have been identified and cloned. This field of cancer metastasis research is now universally recognized as a fundamentally important cellular event critical for cancer cell metastasis. In addition, this basic research was translated to the clinic. 1- Based on the original analysis it was concluded that galectin-3 detection is a promising diagnostic tool for improving the clinical management of patients bearing follicular thyroid proliferations. 2- In the search of a competitive non-toxic simple sugar to inhibit galectin-3 function and block metastasis, it was found that most sugars were cleared from the circulation within minutes of introduction and thus were ineffective. A derivative of pectin, when given orally in the drinking water blocks experimental and spontaneous metastasis. Thus, he proposed the introduction of a novel therapy, based on a new paradigm of inhibition of function rather than killing. Consequently, MCP is now in phase II Multicenter clinical trial Cancer Institute
All of the above has provided the framework for the current proposal wherein it is proposed to continue the studies on the role of galectin-3 in tumor progression and metastasis with special emphasis on the translational aspect, which is expected to provide the framework for better diagnosis and rational intervention in cancer metastasis.