Landmarks in Cancer Research: 1907-1960
- Sunlight exposure is linked to skin cancer.
The first epidemiologic study of sunlight and skin cancer was reported; earlier observations had linked chronic skin conditions common in sailors to exposure to the radiation effects of the sun. Later work in animal models confirmed that skin cancer could be induced by ultraviolet light and sunlight. (1)(2)(3)
- American Association for Cancer Research is founded by four surgeons, five pathologists, and two biochemists (right) on May 7 in Washington, DC.
- Japanese cancer journal, Gann: Japanese Journal of Cancer Research (now titled Cancer Science), is first published.
- Nine research papers are presented at the first Annual Meeting of the AACR in New York City.
- Cell-free extracts transmit cancer from one animal to another. Cell-free agents were shown to transmit leukosis, a form of leukemia and lymphoma, and sarcomas in chickens. This finding would later be verified as evidence for viral initiation of cancer. (4)(5)
- Martha Tracy (right), from Women’s Medical College in Philadelphia (later dean of that college), becomes the AACR’s first female member.
- AACR writes President William H. Taft advocating funding for cancer research.
- Procedures for in vitro tissue culture are developed.
The fundamental culture techniques, now ubiquitous in the laboratory, allowed researchers to study the evolution of tumor tissue under known conditions and to observe living cancer cells at every stage of growth. (6)
- French journal, Bulletin de l’Association Française pour l’Étude du Cancer, and the Italian journal, Tumori, are first published.
- AACR member Thomas S. Cullen, MD, presents “Education of the People as to What Can Be Done in Early Cases of Cancer” at the Annual Meeting.
This appeal for public education led the Ladies’ Home Journal to publish “What Can We Do About Cancer,” the first consumer-oriented article about cancer.
- A group of volunteers—including AACR founding member and past president James Ewing—establishes the American Society for the Control of Cancer (right), precursor to the American Cancer Society.
- Alterations in chromosomes are postulated to cause tumor growth.
From earlier work on sea urchin eggs and association of inappropriate segregation of chromosomes and changes in cell growth characteristics came the hypothesis that cancer was caused by abnormal chromosomes. (7)
- First experimental animal model of chemically induced cancer is developed.
Repeated tarring of rabbit skin caused tumors. The discovery added to early evidence for the theory of chemical carcinogenesis, building upon the observation in 1775 of scrotal cancer in chimney sweeps. Later work published in the AACR’s The Journal of Cancer Research would isolate and identify the specific components of coal tar responsible. (8)(9)
- AACR begins publishing The Journal of Cancer Research, the first English language cancer journal.
- Oophorectomy decreases breast cancer in mice.
Removal of the ovaries from female mice of a strain with a high incidence of spontaneous breast cancer resulted in a decrease in tumors. Later work published in The Journal of Cancer Research involving transplantation of ovaries into male mice showed an induction of mammary tumors, supporting the suggestion that hormones from the ovary could promote breast tumors. (10)(11)
- American Society for the Control of Cancer creates the first National Cancer Week as an extensive public education campaign.
- U.S. Public Health Service opens Office of Cancer Investigations at Harvard Medical School.
- Metabolic studies show that tumors exhibit anaerobic respiration.
Whereas normal tissues use oxygen to break down nutrients for growth as their primary mode of respiration, it was observed that within tumors, cells respire anaerobically, fermenting sugars without oxygen. It will take several decades before hypoxia is revisited as a marker for tumors. (12)(13)
- Cancer is named one of the top three causes of death in America by U.S. Census Bureau.
- Genetic mutation is proposed as the origin of cancer.
As an alternative to the infection theory of cancer, popular at the time because of the expansion of microbiology as a field of study, came the proposal that somatic mutation was the cause of cancer. As Mendel’s works were rediscovered in 1928, the field of genetics grew. The term “somatic mutation” had been coined in 1916. (14)(15)
- Cervical cancer cells are visible in smears of exfoliated vaginal cells.
Findings of cervical cancer cells in smears were met with skepticism, and it would take until the 1960s before the “Pap” smear would become widely accepted as an effective method of screening and cancer prevention. (16)(17)
- X-rays are shown to be mutagenic.
X-rays were shown to be mutagenic in the common fruit fly. This discovery formed the basis for thinking about how carcinogens participate in tumorigenesis. (18)
- First pure carcinogen, benzopyrene, is isolated from coal tar.
The known cancer-causing environmental substance, coal tar, was fractionated into components and assayed in mouse models to identify the individual chemicals responsible for carcinogenesis. (19)
- Ransdell Act establishes the National Institute of Health.
- The American Journal of Cancer replaces The Journal of Cancer Research as the official AACR publication.
- Injected synthetic hormones induce breast cancer in mice.
Building on work on endogenous hormones, it was demonstrated that addition of synthetic exogenous hormones such as folliculin (and in 1952, diethylstilbestrol) can induce cancer. (20)(21)
- Electron microscope is invented.
The electron microscope permitted the visualization of minute subcellular structures, allowing observation of detailed differences between malignant and normal tissues. (22)
- National Cancer Institute Act establishes the National Cancer Institute (NCI) as an independent research institution.
- Transplantation of a single leukemic cell transmits leukemia in mice.
Studies published in AACR’s The American Journal of Cancer showed that not all cancer cells behaved in an identical manner; some were uniquely capable of initiating and maintaining a tumor. This work laid the foundation for the later search for a cancer stem cell. (23)
- Telomeres are identified.
The ends of chromosomes were shown to be protected by a structure that prevented their fusion. Later, it was shown that telomeres are repeated simple sequence elements that are added by an enzyme, telomerase, which is not normally expressed in somatic cells. In each cell division, telomeres shorten. When they become sufficiently truncated they cause the cells to enter into senescence and die, limiting the number of divisions a cell can undergo and suppressing tumor development. (24)(25)(26)
- Discovery of antigens explains why tumors can be transplanted within inbred strains.
Previous work to transplant tumors had been successful in some instances but failed in others. The discovery of major histocompatibility antigens later led to an immunologic explanation that applied to grafts of normal tissue as well as to malignant tissue. (27)(28)
- Chemicals induce cancer in two distinct steps of initiation and promotion.
Tumorigenesis was identified as a multistage disease, and it was shown that chemicals induce cancer in two distinct steps of initiation and promotion. A nonspecific irritant (wounding) was shown to promote tumorigenesis after initiation with a suboptimal dose of carcinogen (tarring or application of Shope papillomavirus to rabbit ears). Further study of the significance of cocarcinogenic action was later published in Cancer Research. (29)(30)
- Transplanted animal tumors are shown to grow blood vessels.
Tumors transplanted into the ears of rabbits elicited a vascular network. This was early evidence of the phenomenon of angiogenesis, or new blood vessel growth, which would later become a target for antiangiogenesis cancer therapies. (31)
- Caloric restriction reduces tumors in mice.
Studies published in The American Journal of Cancer and later in Cancer Research showed that caloric intake was proportional to the incidence of tumors of several kinds, including spontaneous mammary carcinomas and hepatomas in susceptible mouse strains and benzopyrene-induced skin tumors. Only recently, with the increasing prevalence of obesity in the global population, have the implications of the work been revisited. (32,33)
- Cancer Research replaces The American Journal of Cancer as AACR’s official journal.
- Hormone dependence of prostate cancer is demonstrated.
In a study published in Cancer Research, the therapeutic use of physical castration or chemical castration by treatment with estrogens was shown to decrease disease burden in metastatic prostate cancer whereas injection of androgens increased metastases. (34)
- DNA is identified as the active material in the genes of bacteria.
It was not known whether the protein or DNA components of the chromosomes contained the information necessary for inheritance. This work showed that DNA contained the heritable information and set the stage for many important works and techniques. (35)
- American Society for the Control of Cancer becomes the American Cancer Society.
- Public Health Services Act designates NCI as a division of the National Institutes of Health (NIH).
- Atomic Bomb Casualty Commission is established to monitor the effects of radiation exposure.
- Nitrogen mustard is established as the first chemotherapeutic agent.
Observational reports that soldiers exposed to nitrogen mustard during wartime had low white blood cell counts led to testing of nitrogen mustard as chemotherapy for cancer. Intravenous nitrogen mustard was shown to slow the growth of lymphomas and leukemias in patients refractory to radiation therapy, and it achieved remissions of a few months. Nitrogen mustard was approved for cancer treatment in 1949. (36)
- Nuremberg Code establishes the legal principle of voluntary consent for human subjects of research.
- At the 38th AACR Annual Meeting, May 16-17, a policy presentation titled, “On the Organization and Support of Cancer Research,” concludes that the AACR should advocate for increased funding for cancer research.
- First successful chemotherapy for childhood leukemia is reported.
A synthetic folate antagonist achieved a three-month remission in 10 of 16 children with leukemia. Although not successful by today’s standards, this was an important result that would lead to further work on antimetabolites and the first generation of effective chemotherapeutic agents. (37)
- United Nations establishes the World Health Organization.
- First rationally conceived nucleotide analog chemotherapeutic agents are developed.
Drug design had been primarily by trial and error. The design of molecules similar to the bases of DNA, but sufficiently different to prevent replication, proved an effective drug targeting approach that led to several chemotherapeutic drugs for cancer such as 6-mercaptopurine and 5-fluorouracil, which are still in use today. (38,39)
- Epidemiologic work links tobacco smoking to lung cancer.
A retrospective analysis of the smoking habits of patients with lung cancer showed an association with tobacco. This was followed by a prospective study of male doctors that showed a clear relationship between smoking and lung cancer deaths. Tobacco exposure is now a known risk factor for many cancer types, accounting for an estimated 30% of all cancer mortality. (40-42)
- Leukemia in mice is shown to be transmissible by a virus.
Leukemia had been considered an inherited disease before it was shown that it could be transmitted from one mouse strain to another by a virus and then passed from one generation to another via vertical transmission. These findings laid the groundwork for later research on other mouse tumor viruses and those in other species. (43)
- Cobalt-60 irradiator is developed.
Radiotherapy previously had been carried out using radium, which was in limited supply and needed to be used in close proximity to the tumor. Radioactive cobalt provided a continuous source with greater ability to treat internal tumors, with less damage to the intervening tissue. Clinical cobalt-60 is still used in much of the developing world. (44)
- Ultrasound imaging is developed for detecting tumors.
Although earlier studies had used ultrasound as a therapy and had examined its use as an imaging tool, research showed that ultrasound could detect differences in density between malignant and normal tissues. (45)
- AACR Annual Meeting abstracts are published for the first time as Proceedings of the American Association for Cancer Research (154 abstracts).
- Structure of DNA is described.
Not only was the global structure of DNA identified, but how the bases pair and possible implications for methods of replication were also elucidated. (46)
- Human carcinoma cell line, HeLa, is established from the cells of Ms. Henrietta Lacks.
The HeLa epithelial cell line is readily grown in laboratories worldwide and has become a fundamental tool for studying many aspects of molecular biology. Stable cell lines such as HeLa allow researchers to use genetically identical cells for experiments over long-term courses of repeated culturing in a manner not possible with primary cells. (47)
- Medical linear accelerator is developed for radiotherapy.
Unlike early radiotherapy machines that used a radioactive source to generate X-rays, the linear accelerator produces a beam of electrons. This eliminated the need to replace the radioactive source and is limited in power by the length of the accelerator tube. (48)
- Tumor clonogenic assay is developed.
Although human cells had been cultured before, these new methods allowed cultures to be propagated from single human cells, enabling the kind of detailed genetic studies previously only possible for bacterial cells. (49)
- U.S. Congress funds National Chemotherapy Program to test compounds that might be effective against cancer.
- First successful chemotherapy for solid tumors is reported.
Building on earlier work on folate and aminopterin, another antifolate, methotrexate, was developed.The drug was shown to be effective in a small group of three patients with metastatic choriocarcinoma and chorioadenoma. (50)
- Elizabeth C. Miller (right) is the first woman elected to the AACR Board of Directors.
- Association of American Cancer Institutes (AACI) is founded.
Its mission is to reduce the burden of cancer by enhancing the impact of North America’s leading academic cancer centers.
- Food Additives Amendment prohibits food additives shown to induce cancer in humans or animals.
- AACR membership passes 1,000.
- In vitro viral carcinogenesis is demonstrated.
Earlier work had shown that viruses could be used to transmit cancer from one organism to another. New studies showed that chick embryo cells infected with Rous sarcoma virus continued to grow in culture and produce more virus. The infected cells had changes in morphology and rapid, disordered growth characteristic of cancer cells. (51)
- DNA repair after radiation is demonstrated.
Chinese hamster ovary cells subjected to X-irradiation and surviving did not display heritable damage but repaired the damage prior to cell division. This finding confirmed the presence of DNA repair mechanisms, later shown to be defective in some cancers. (52)
- Dose-response relationship is shown in radiation-induced leukemia.
Radiation carcinogenesis was unequivocally established in human populations, and the nature of the dose-response relationship was described. (53)
- Radioimmunoassay is developed.
The radioimmunoassay uses antibodies to detect the amounts of specific proteins in a solution. Originally developed to measure insulin levels in the blood of diabetics, this technique is now the basis for diagnostic tests to measure serum proteins and biomarkers, such as prostate-specific antigen, although now the detection mechanism often uses fluorescent rather than radioactive labeling. (54)
- American Cancer Society urges widespread use of Pap smear to detect cervical and uterine cancers.
- Philadelphia chromosome is discovered.
An abnormally small chromosome was identified in the neoplastic cells of patients with chronic myelogenous leukemia. This small chromosome, later named the Philadelphia chromosome after the city in which it was discovered, was the first chromosomal abnormality found to be consistently associated with a specific human neoplasm. (55)
- Growth factors are purified and identified.
The fact that growth factors were necessary for cells to survive and replicate had long been known, but the individual components of serum responsible had not been identified. The purification of nerve-growth factor led to the identification of other growth factors, their cognate receptors, and their complex signaling pathways. These pathways have emerged as novel targets for therapies such as those targeting the epidermal growth factor receptor (EGFR). (56)
- Screening techniques for prevention of colon cancer are adopted.
The sigmoidoscope permitted early identification of colorectal cancer as well as precancerous polyps, leading to increased survival rates. It is estimated that screening by sigmoidoscopy, colonoscopy, barium enema, or fecal occult blood testing may result in a 20% decrease in colorectal cancer mortality. (57,58)
- Dubreuilh W. Epitheliomatose d’origine solaire. Ann Dermatol Syphiligr 1907;8:387–416.
- Findlay GM. Ultra-violet light and skin cancer. Lancet 1928;212:1070–3.
- Roffo AH. Krebs und sarkom durch ultraviolett- und sonnenstrahlen. Z Krebsforsch 1935;41:448–67.
- Ellermann V, Bang O. Experimentelle leukamie bei huhnern. Erscheinungsort nicht ermittelbar. Vorlaufige Mitteilung Centralbl f Bakteriol 1908; xlvi, 4.
- Rous P. A transmissible avian neoplasm (sarcoma of the common fowl). J Exp Med 1910;12:696–705.
- Carrel A, Burrows MT. Cultivation of sarcoma outside of the body: a second note. JAMA 1910;55:1554.
- Boveri T. Zur frage der entstehung maligner tumoren. Jena, Germany: Gustav Fisher; 1914.
- Yamagiwa K, Ichikawa K. [Repeated painting of coal tar onto rabbits’ ears causes carcinomas]. J Imperial Univ Tokyo 1915;15:295−344.
- Yamagiwa K, Ichikawa K. Experimental study of the pathogenesis of carcinoma. CA Cancer J Clin 1977;27:174−81.
- Lathrop AE, Loeb L. Further investigations on the origin of tumors in mice. III. On the part played by internal secretion in the spontaneous development of tumors. Cancer Res 1916;1:1−19.
- Murray WS. Ovarian secretion and tumor incidence. Cancer Res 1928;12:18−25.
- Warburg O, Posener K, Negelein E. [VII. The metabolism of the cancer cell]. Biochem Z 1924;152:319−44.
- Weinhouse S. On respiratory impairment in cancer cells. Science 1956;124:267−9.
- Bauer KH. Mutationstheorie der geschwulst-entstehung. Berlin, Germany: Springer; 1928.
- Tyzzer EE. Tumor immunity. Cancer Res 1916;1:125−56.
- Papanicolaou GN. New cancer diagnosis. CA Cancer J Clin 1973;23:174−9.
- Papanicolaou GN. A survey of the actualities and potentialities of exfoliative cytology in cancer diagnosis. Ann Intern Med 1949;31:661−74.
- Muller HJ. The production of mutations by X-rays. Proc Natl Acad Sci U S A 1928;14:714−26.
- Kennaway EL. Further experiments on cancer-producing substances. Biochem J 1930;24:497−504.
- Lacassagne MA. [Appearance of mammary cancers in male mice subjected to folliculin injections]. Comptes Rendus de l’Academie des Sciences 1932;195:630−2.
- Dunning WF, Curtis MR. The incidence of diethylstilbestrol-induced cancer in reciprocal F hybrids obtained from crosses between rats of inbred lines that are susceptible and resistant to the induction of mammary cancer by this agent. Cancer Res 1952;12:702−6.
- Knoll M, Ruska E. Das elektronenmikroskop. Zeitschrift für Physik 1932;78:318−39.
- Furth J, Kahn MC, Breedis C. The transmission of leukemia of mice with a single cell. Am J Cancer 1937;31:276−82.
- McClintock B. The fusion of broken ends of sister half-chromatids following chromatid breakage at meiotic anaphases [dissertation]. Columbia, MO: University of Missouri; 1938.
- McClintock B. The discovery and characterization of transposable elements: the collected papers of Barbara McClintock. New York: Garland Publishing; 1987.
- Müller HJ. The remaking of chromosomes. Collecting Net 1938;13:181−98.
- Gorer PA. The genetic and antigenic basis of tumour transplantation. J Pathol Bacteriol 1937;44:691−7.
- Gorer PA, Lyman S, Snell GD. Studies on the genetic and antigenic basis of tumour transplantation linkage between a histocompatibility gene and “fused” in mice. Proc R Soc Lond B Biol Sci 1948;135:499−505.
- Kidd JG, Rous P. The carcinogenic effect of a papilloma virus on the tarred skin of rabbits: II. Major factors determining the phenomenon: the manifold effects of tarring. J Exp Med 1938;68:529−62.
- Berenblum I. The mechanism of carcinogenesis. A study of the significance of cocarcinogenic action and related phenomena. Cancer Res 1941;1:807−14.
- Ide AG, Baker NH, Warren SL. Vascularization of the brown Pearce rabbit epithelioma transplant as seen in the transparent ear chamber. Am J Roentgenol 1939;42:891−9.
- Tannenbaum A. The initiation and growth of tumors. Introduction. I. Effects of underfeeding. Am J Cancer 1940;38:335−50.
- Tannenbaum A, Silverstone H. The influence of the degree of caloric restriction on the formation of skin tumors and hepatomas in mice. Cancer Res 1949;9:724−7.
- Huggins C, Hodges CV. Studies on prostatic cancer. I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res 1941;1:293−7.
- Avery OT, Macleod CM, McCarty M. Studies on the chemical nature of the substance inducing transformation of pneumococcal types: induction of transformation by a deoxyribonucleic acid fraction isolated from pneumococcus type III. J Exp Med 1944;79:137−58.
- Goodman LS, Wintrobe MM, Dameshek W, Goodman MJ, Gilman A, McLennan MT. Nitrogen mustard therapy. Use of methyl-bis(beta-chloroethyl)amine hydrochloride and tris(beta-chloroethyl)amine hydrochloride for Hodgkin’s disease, lymphosarcoma, leukemia and certain allied and miscellaneous disorders. JAMA 1946;132:126−32.
- Farber S, Diamond LK. Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid. N Engl J Med 1948;238:787−93.
- Hitchings GH, Elion GB, Falco EA, Russell PB, Sherwood MB, Vanderwerff H. Antagonists of nucleic acid derivatives: I. The Lactobacillus casei model. J Biol Chem 1950;183:1−9.
- Heidelberger C, Chaudhuri NK, Danneberg P, Mooren D, Griesbach L, Duschinsky R, et al. Fluorinated pyrimidines, a new class of tumour-inhibitory compounds. Nature 1957;179:663−6.
- Doll R, Hill AB. Smoking and carcinoma of the lung; preliminary report. Br Med J 1950;2:739−48.
- Doll R, Hill AB. The mortality of doctors in relation to their smoking habits; a preliminary report. Br Med J 1954;1:1451−5.
- Doll R, Hill AB. Lung cancer and other causes of death in relation to smoking; a second report on the mortality of British doctors. Br Med J 1956;2:1071−81.
- Eddy BE, Stewart SE, Berkeley W. Cytopathogenicity in tissue culture by a tumor virus from mice. Proc Soc Exp Biol Med 1958;98:848−51.
- Johns HE, Bates LM, Epp ER, Cormack DV, Fedorux SO, Morrison A, et al. 1,000-curie cobalt 60 units for radiation therapy. Nature 1951;168:1035−6.
- French LA, Wild JJ, Neal D. Detection of cerebral tumors by ultrasonic pulses; pilot studies on postmortem material. Cancer 1950;3:705−8.
- Watson JD, Crick FH. Molecular structure of nucleic acids: a structure for deoxyribose nucleic acid. Nature 1953;171:737−8.
- Scherer WF, Syverton JT, Gey GO. Studies on the propagation in vitro of poliomyelitis viruses. IV. Viral multiplication in a stable strain of human malignant epithelial cells (strain HeLa) derived from an epidermoid carcinoma of the cervix. J Exp Med 1953;97:695−710.
- Miller CW. Travelling-wave linear accelerator for X-ray therapy. Nature 1953;171:297−8.
- Puck TT, Marcus PI. A rapid method for viable cell titration and clone production with HeLa cells in tissue culture: the use of X-irradiated cells to supply conditioning factors. Proc Natl Acad Sci U S A 1955;41:432−7.
- Hertz R, Li MC, Spencer DB. Effect of methotrexate therapy upon choriocarcinoma and chorioadenoma. Proc Soc Exp Biol Med 1956;93:361−6.
- Vigier P, Golde A. Growth curve of Rous sarcoma virus on chick embryo cells in vitro. Virology 1959;8:60−79.
- Elkind MM, Sutton H. X-ray damage and recovery in mammalian cells in culture. Nature 1959;184:1293−5.
- Armitage P, Court Brown WM, Doll R, Mewissen DJ. Dose-response relationship in radiation leukaemia. Nature 1959;184:1669−70.
- Yalow RS, Berson SA. Assay of plasma insulin in human subjects by immunological methods. Nature 1959;184:1648−9.
- Nowell PC, Hungerford DA. A minute chromosome in human chronic granulocytic leukemia. Science 1960;132:1497.
- Cohen S. Purification of a nerve-growth promoting protein from the mouse salivary gland and its neuro-cytotoxic antiserum. Proc Natl Acad Sci U S A 1960;46:302−11.
- Cameron AB, Thabet RJ. Sigmoidoscopy as part of routine cancer clinic examinations with correlated fecal chemistry and colon cytologic studies. Surgery 1960;48:344−50.
- Vogelaar I, van Ballegooijen M, Schrag D, Boer R, Winawer SJ, Habbema JD, et al. How much can current interventions reduce colorectal cancer mortality in the U.S.? Mortality projections for scenarios of risk-factor modification, screening, and treatment. Cancer 2006;107:1624−33.