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The Cancer Journal - Volume 9, Number 4 (July-August 1996)


Cytokines and cancers - extracting the melody from background noise

For many years, a cherished expression of immunologists was 'host-tumour relationships' by which they essentially meant the ability of various lymphocyte and macrophage populations to destroy tumour cells and to inhibit or stimulate their growth, either with or without the participation of antibodies, lymphokines and monokines.

The study of host-tumour interactions has gradually broadened with the description of an increasing number of cytokines. These are produced by immunocompetent cells - or by many other differentiated cells that strictly speaking are outside the immune system - and are able to act on functions involved in tumour growth and dissemination. About one hundred have been characterized, isolated, assayed and produced industrially but this number is continually on the increase. Other molecules besides cytokines also partake in intercellular and intertissular exchanges, in the maintenance of tissue structure, or in its repair during remission. These are, for instance, hormones, growth and differentiation factors, and their receptors.

Our knowledge of the involvement of cytokines and these other molecules in cancer diseases remains fragmentary. Some cytokines have been assayed in the tumor tissue or serum of patients in order to explore inflammatory response, neo-angiogenesis, antitumour immune response or other phenomena in which they are thought to be implicated. The usual aim was to elucidate some aspect of a mechanism involved in the progression of a specific form of cancer. Cytokines (interferon, IL-2 ...) have been administered alone or in combination with other treatments in large-scale clinical trials.

Whether implicitly or explicitly, many researchers believe and/or suppose that informational molecules such as cytokines and hormones play a role in cancer physiopathology. Each known cytokine participates in diverse functions and, as a result of this diversity, is linked with disciplines sometimes far removed from cancerology. A global view of their functions thus quickly becomes fuzzy.

Instead of starting, as many laboratories do, from one of the mechanisms of carcinogenesis in which cytokines might be involved and investigating the dynamics of this relation, we propose the reverse strategy. Let's consider two fields, that of cancers and that of cytokines and other 'hormones'. Can one experimentally identify the overlap/intersection between these two fields and how it is organized by describing the structure of the overall system formed by the two fields ? In practice, we are suggesting a two-step approach which should not exclude a priori any particular cytokine (or hormone) nor any human cancer correctly staged according to the TNM classification system and characterized by its histology and rate of progression,.The decision to include a cytokine or hormone will, in fact, depend only on the availibility of the necessary reagent, the reliability of the test, and the ability to perform these tests on a routine basis. The two steps are : 1) systematic screening assays on tumour tissue, serum and, when available, healthy tissue; 2) appropriate multivariate data analyses that highlight the structure of the system. This should enable us to find out whether the observed structure, and overlap if any, is organised in a way that is accessible to our understanding or intuition.

An underlying rationale of this systematic and systemic approach to rethinking host-tumour relationships is the need to exploit, to the full and without further delay, a biotechnological tool that is available but underused. No coherent overview can be obtained by just assembling available heterogenous data. Instead, one must create a data bank specifically tailored to the needs of the project and which meets the necessary criteria of data homogeneity and exhaustivity. Only thus can one expect to delineate profiles of biological variation that might correspond to symptom or syndrome profiles. It is our hope that the knowledge gained may give a new impetus to therapeutic innovation and permit more cogent applications of cytokine combinations in anticancer treatment.

Jean-Claude Salomon