Neoplastic Progression 1954

The ability to observe the growth of neoplasms in animals brought new concepts to experimental cancer research. From the very beginning of experimental cancer research, mice have been used to determine the origins of tumors and to watch how they evolve from benign (in situ) to invasive and from progress to metastatic. One key concept was that tumors do progress through stages. The term "progression" was first applied to virus-induced papillomas and carcinomas by Rous and Beard (Rous and Beard, 1935; Rubin, 1994). However, the seminal papers on the subject came in the 1950s from Leslie Foulds who used the mouse mammary tumor system for his experimental model. He articulated and, in his own way, carefully defended six rules of neoplastic progression (Foulds, 1954):

Rule I: Progression occurs independently in different tumors in the same animal.

Rule II: Progression occurs independently in different characters in the same tumor.

Rule III: Progression is independent of growth. It occurs in latent tumor cells and in tumors whose growth is arrested.

Rule IV: Progression is continuous or discontinuous, by gradual change or by abrupt steps.

Rule V: Progression follows one of alternative paths of development.

Rule VI: Progression does not always reach an end point within the lifetime of the animal.

The reader should remember that the Papanicolaou and Trout monograph on cervical cytology to detect precancers of the cervix only appeared in 1943 (Papanicolaou and Traut, 1943) and the "Pap Smear" did not have widespread acceptance when Foulds' 1954 paper appeared (Shimkin, 1977a). However, the Pap Smear has saved countless lives from cervical cancer and became the basis for early cytological detection of cancers of many other origins. The theme of early detection is now the mantra for the American Cancer Society and NCI.

Foulds' ideas were primarily based on his observations of hormone-dependent mammary tumors in RIII x Black 6 mice that he named "BR" (Foulds, 1949, 1954, 1959). The tumors, Foulds observed, were initially hormone dependent (plaques) but frequently evolved into hormone-independent tumors. Foulds, a medical pathologist as well as a tumor biologist, developed these concepts and expanded them into a two volume treatise on "Neoplastic Development" (Foulds, 1959, 1975). His concepts were consistent with the morphological observations of the tumors in human and mouse. They complied with the ideas of initiation and promotion applied to carcinogen-induced skin tumors in the mouse (Berenblum and Shubik, 1954; Rous and Beard, 1935; Shubik, 1950; Shubik et al., 1953). Interestingly, the terms initiation and promotion were also introduced by Rous (Foulds, 1954) in describing experiments with chemical carcinogens in the rabbit. These concepts were later applied to the mouse (Rous and Kidd, 1941).

Further, this idea fits well into the concepts of linear progression and clonal evolution currently in vogue in human colon and breast cancer (Burstein et al., 2004; Fearon and Vogelstein, 1990). The observations of heterogeneity in induced MMTV tumors by Heppner and her group in Detroit during the 1980s also seem consistent with Foulds' observations (Heppner, 1972; Michalides et al., 1982). Not all of Foulds' rules were accepted by the scientific community. For example, Rubin, basing his criticism on spontaneous in vitro transformation of fibroblasts, contested Foulds' rules number III, IV, and V (Rubin, 1994).

Developed during an era in which the Willis "field effect" was the prevailing hypothesis for tumor origin, Foulds' diagrams of progression leave open the possibility of a unicellular origin, although one cannot find mention of the clonal origin of cancer in Foulds' own essays (Foulds, 1959; Willis, 1953).


Although the term "progression" was first applied to neoplasia by Rous and Beard in a study of the evolution of rabbit papillomas to invasive cancers (Rous and Beard, 1935; Rubin, 1994), observation of the mouse mammary gland has long been favored to understand neoplastic progression. Foulds' hypothesis was built on the evolution of mouse mammary tumors. Other investigators were more interested in the origin of the tumor.

The early literature is interesting in that some investigators were correct and others were just confused. Breast cancer itself had been known since antiquity. However, the origin of breast cancer, or any other cancer, remained obscure with a variety of imaginative hypotheses extant. Remember that in 1850, the difference between true cancer and chronic inflammation was not completely understood. The light microscope added a new dimension. Even then, authorities such as Virchow maintained that all cancers arose from connective tissues (Rather, 1978). This idea was a reasonable hypothesis given the dense connective tissue stroma associated with most cancers.

The German pathologist Waldeyer first accurately described the origin of epithelial cancers although he was using primitive histological techniques and microscopes. He used microscopic slides of colon and breast for evidence that human cancers arose from preexisting epithelium (Rather, 1978; Waldeyer, 1867). He invoked the same line of reasoning used today. That is, that the breast cancer arose in direct continuity with preexisting mammary acini. The acini were themselves atypical. Although others such as Connheim continued to hypothesize embryonic rests, Waldeyer's observations were eventually confirmed and accepted by others. When Elberth and Spude examined mouse mammary tumors in 1898, they did not observe direct connections with the mammary epithelium and classified the mouse tumors as "endotheliomas" (Eberth and Spude, 1898). This diagnosis was disputed by Apolant and Haaland but neither was able to demonstrate direct continuity with the normal mammary gland (Haaland, 1911), which was subsequently demonstrated by others (Woglom, 1913).

It is difficult to ascertain the scientific context during these years. Human breast cancer had long been associated with chronic mastitis. In 1913, James Ewing delivered an address to the New York Medical Society entitled "Precancerous Diseases and Precancerous Lesions: Particular in the Breast (Ewing, 1914). In this essay he credits his German mentor, Orth, for the term "precancerous diseases." Orth himself was a distinguished German pathologist who was Virchow's successor. The point here is that the term "precancer" was being used at the turn of the twentieth century. Medical scientists were thinking about precancers 100 years ago.

Apolant, working with Paul Ehrlich, also identified a smaller lesion he called adenomen or adenoma simplex (Apolant, 1906). He falls short of declaring that these lesions were precancers and did not show a clear relationship between these lesions and larger tumors. His colleague (Haaland, 1911), in 1911, not only redescribed Apolant's lesions but wrote a lengthy section on these hyperplastic nodules and their biological potential. Although he did not directly use the term, Haaland's discussion leaves no question that they were precancerous (Haaland, 1911).

Subsequent descriptions by Fekete and others in the late 1930s associated the hyperplastic nodules with the subsequent development of mammary cancers (Fekete, 1938). MMTV infection and hormones were associated with adenomas or adenomatous nodules by Pullinger (1947). While many investigators could relate the presence of HAN to the tumor incidence and the presence or absence of MMTV, others were not able to confirm the association because they found "nodules" in elderly, low-incident mice and in carcinogen-treated and irradiated mice (Dunn, 1945, 1958). It was also very clear that more HAN were present in each mouse than tumors. So, by 1959, the biological potential of the lesions was still a hotly disputed subject with many conflicting lines of evidence. Dr. Dunn, who had a knack for such terminology, cleverly entitled her section on this topic "Preneoplastic and early neoplastic changes (Dunn, 1958)."

The controversies over which lesions, if any, were precursors to cancer were subsequently eliminated by De Ome using his technique for transplantation into a gland-cleared fat pad. His studies provided definitive experimental proof that the HAN were in fact the precursor tissues to mouse mammary cancers (De Ome et al., 1959). Interestingly, De Ome used the term "precancer" in his original 1959 paper. The first time "pre-neoplasia" appears in the De Ome HAN literature was in 1961 (De Ome et al., 1961).

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