Foreword

Back in 1863 Rudolf Virchow, the founder of modern pathology, observed leukocytes nesting in neoplastic tissues ("lymphoreticular infiltrate" in his words). Consequently, he suggested that cancer may arise at sites of chronic irritation. This is how the link between inflammation and cancer was born. Hundred and fifty years later, cancer researches and pathologists have begun to appreciate the significance of the inflammation-cancer nexus. Even though a "lymphoreticular infiltrate" in tumors is often invisible, it is likely that inflammation plays a role in most tumors. However, it remained to determine whether inflammation in cancer is good for the patient and bad for the tumor, or vice versa. In this regard, we have witnessed in recent years a paradigm shift. The dogma prevailing until the turn of the 20th century was that inflammation and immunity play their classical protective role by defeating cancer like pathogens. This view was profoundly outlined in the "cancer immunosurveillance" theory formulated in 1957 by Burnet and Thomas. These two protagonists of the field proposed that lymphocytes act as sentinels in recognizing and eliminating nascent transformed cells that arise frequently in mammalian tissues. However, epidemiological, experimental and clinical evidence failed to support this notion. Numerous studies have demonstrated that immune-deficient humans and mice do not develop cancer at a higher frequency than their normal counterparts, yet, surprisingly, all these negative data only intensified the efforts to reinforce a cancer-debilitated immune system. Immuno-adjuvants, in vivo and ex-vivo immune stimulation by native or modified tumor cells and other attempts to mobilize the immune system in the fight against cancer have commonly failed. But these frustrating efforts have not been in vein. They cultivated novel and heretic trends, beginning by forsaking the cancer immunosurveillance theory and ending with the advancement of initially provocative views, implying that immunity and inflammation may inadvertently serve the tumor rather the host.

What have we learned recently about immunity and inflammation in cancer? We realized that inflammatory cells and cytokines at the tumor microenvironment are more likely to enhance, rather than curb tumor progression and may even induce local immunosuppression. We also understood that cancer susceptibility is often associated with functional polymorphism of pro-inflammatory cytokine genes, and that depriving the tumor of pro-inflammatory cytokines retards its progression in experimental models. A notable example is TNF, once perceived as its acronym stands for: tumor necrosis factor. Today, however, TNF is an outstanding example for a tumor promoting factor. Based on this rising evidence, Mantovani and Balkwill denoted cancer promoting mutations as "the match that lights the fire”, whereas inflammation, chemokine and cytokines would be the “fuel that feeds the flames”.

Hence, the time is ripe to review the mounting knowledge of cytokines and chemokines in the context of cancer and draw the insights required to harness this knowledge for cancer therapy. This eBook on “The Inflammatory Milieu of Tumors: Cytokines and Chemokines”, edited by Adit Ben-Baruch, is an important step in that direction. It provides an updated overview of tumor-infiltrating cells and soluble mediators, while highlighting their role in cancer. It also outlines intervention modes in experimental systems, aiming to turn the microenvironment against the tumor.

We have learned a great deal about the nature, sources and purpose of Virchow's "lymphoreticular infiltrate". The challenge of the future is to develop the means for taming the immune system to extinguish, rather than feed the deadly flames of cancer. Hopefully, readers of this eBook will gain ideas and insights as to how to cope with this challenge.