History Of Mononuclear Cell Infiltration In Cancer

Mononuclear cell infiltration is a common feature of many types of human cancers. In fact, its occurrence is considered so unremarkable that there are no systematic studies describing the prevalence or intensity of infiltrates by tumor type or stage. Instead, it is generally asserted that intense infiltrates are associated with certain tumor types, such as medullary carcinoma of the breast and malignant melanoma (1,2), and that most other cancers are also infiltrated to differing extents. Even without an "epidemiology" of tumor-related inflammatory infiltrates, tumor biologists have extensively focused on this phenomenon for more than 100 yr.

Leukocyte infiltration in cancer has been appreciated since the beginning of microscopic analyses of human tumors, but controversy surrounded the question of its origin and the causal relationship in which it stands to carcinogenesis. Virchow (3) first described the association of inflammatory cells with human tumors and inferred that cancers arose from transformed connective tissue elements (including leukocytes) at sites of chronic inflammation. Later, Waldeyer (4) argued more persuasively for homotypic tissue sources for malignancy, e.g., carcinomas derived from transformed epithelial cells. Nonetheless, he and others asserted that the infiltrative component was an integral and causal part of the tumor.

Not until the early 1900s could some of these issues be resolved through the analysis of transplantable tumors in animals. Jensen (5) used a murine tumor to demonstrate that tumor tissue in the recipient animal was derived from injected tumor cells rather than the host. Bashford (6) used Jensen's tumor and other models to show that donor stroma contaminating the injected tumor dies after inoculation, and thus the stroma surrounding and infiltrating the mature tumor in the recipient was derived from the recipient host rather than the donor tumor. This stroma was examined in detail by Russell (7), who coined the term stromal reaction to describe the collection of mono-nuclear cells, fibroblasts, and connective tissue elements elicited by a transplanted tumor in a susceptible host. A more thorough analysis of the stromal reaction in transplanted murine tumors was provided by Da Fano (8). In fully developed tumors, he described an infiltration by "lymphocytes" and large numbers of the "quiescent wan-

From: Chemokines and Cancer Edited by: B. J. Rollins © Humana Press Inc., Totowa, NJ

dering cells" of Maximow, which have a monocyte-like morphology and were later shown to stain for nonspecific esterase (9). Similar observations were made by Wade (10), in his analysis of transplantable sarcomas in dogs.

In susceptible animals, i.e., those that did not reject tumors, Russell was careful to point out that the character of the stromal response could vary among different tumor types. Notably, however, the characteristic stromal reaction was tumor-type specific and remained constant during subsequent passage of the tumor in different animals. For example, tumors that elicited highly cellular stromal reactions always did so. This led Russell to postulate, for the first time, that tumors might have specific "chemotac-tic" properties that elicit a characteristic stromal reaction. (A similar chemotactic property was suggested to account for capillary ingrowth both by Russell and Ehrlich, anticipating the recent interest in tumor angiogenesis by 75 yr [11].) Still, the general consensus was that the stromal reaction was necessary to support malignant growth. Thus, in immunized animals that rejected tumors, the mechanism of resistance was believed to be the inability of the tumor to induce the development of a properly organized stroma (7,8).

During the first half of the twentieth century, as most of these studies were being performed, there was little precision in identifying leukocytes involved in tumor infiltration. However, by the 1950s, stains based on nonspecific esterase activity demonstrated that the "resting wandering cells" surrounding and invading solid tumors were macrophages, and significant numbers could be found in association with human cancers (9). The number of macrophages in these tumors was found to vary widely, and based on enzymatic profiles it could be shown that some of the macrophages associated with tumors were derived from blood monocytes (12). Electron microscopic examination of human tumors confirmed the presence of lymphocytes, macrophages, and plasma cells as common elements in the stroma of human malignancies (1,2,13).

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