The CSC hypothesis: recalling some history

More about the CSC hypothesis: Cancer Stem Cells: Fact or Fiction? by Caroline Brandon, Connecting for Kids, December 26, 2008. Excerpts:

In the 1960s there was an unethical experiment where physicians took cancer cells from various types of malignancies and re-injected these cells back into the original cancer patient or another non-cancerous terminally ill patient. The results from this experiment suggested that those with cancer lacked immunity to the disease while “healthy” individuals carried some immunity to the cancer cells. However, another interesting observation was made throughout the experiments: that it requires millions of cancer cells to initiate the growth of a tumor. It is this observation from which two theories emerged in the decades to come regarding tumor initiation and maintenance.

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I am hopeful that from studies like this [publication in Nature by Quintana et al] that challenge the current cancer stem cell dogma, new creative approaches will be used to uncover the true culprits behind cancer, be it a rare population of stem cells or a more common population yet to be defined.

For some additional relevant commentary, see this previous post: Tumorigenic cells not rare in human melanoma, December 3, 2008.

Comments: One "unethical experiment" of the kind described in the first excerpt is the Jewish Chronic Disease Hospital case. It has been summarized briefly in the section on injections of cancer cells, in notes entitled Nonconsensual Medical Experiments on Human Beings, by Ronald B Standler (notes created Dec 1996). The initial two sentences:

There were intradermal injections of live human cancer cells into 22 chronically ill, debilitated non-cancer patients in 1963 without their consent in the Jewish Chronic Disease Hospital case, to learn if foreign cancer cells would live longer in debilitated non-cancer patients than in patients debilitated by cancer. Lump at injection site disappeared approximately seven weeks after injection.

For a much more detailed discussion of this case from legal and ethical perspectives, see: Experimentation with Human Beings by Jay Katz, Yale University, Russell Sage Foundation, 1972 [PDF, 58 pages]. Chapter 1 is about The Jewish Chronic Disease Hospital Case. The first sentence of this chapter:

In July 1963, three doctors, with approval from the director of medicine of the Jewish Chronic Disease Hospital in Brooklyn, New York, injected "live cancer cells" subcutaneously into twenty-two chronically ill and debilitated patients.

A publication, apparently based on studies of these patients, is: Rejection of cancer homotransplants by patients with debilitating non-neoplastic diseases by Arthur G Levin, D B Custodio, Emanuel E Mandel, Chester M Southam, Ann N Y Acad Sci 1964(Nov 30); 120: 410-23 [PubMed Citation]. The full text isn't publicly accessible. From the Materials and Methods: "The recipients with non-neoplastic diseases were 19 patients at the Jewish Chronic Disease Hospital ..... The homotransplants consisted of subcutaneous injections of two to five million tissue-cultured cells. Three human cell lines of neoplastic origin were used ...". It seems inconceivable in the light of current ethical standards for human experimentation that these studies could have been carried out and published, but they were. Ethical oversight of such studies was minimal then. The summary from this publication:

Summary

Nineteen patients with advanced, debilitating, non-neoplastic diseases were given two subcutaneous homotransplants of tissue-cultured human cancer cells: one of cell line HEp 2, and one of either HEp 3 or RPMI 41. These recipients rejected the homotransplants promptly, as do normal healthy controls, whereas many patients with advanced cancer have an impaired capacity to reject these cell lines.

These findings indicate that the immunological defect which is evidenced by delayed homograft rejection is not merely a consequence of debility and cachexia.

However, although the defect occurs often in patients with advanced cancer, it is not demonstrable in all cancer patients and it cannot be assumed that it is specifically associated with cancer.

The parallelism of homograft rejection, macrophage mobilization, and delayed hypersensitivity response is discussed.

The full text begins with the statement that: "Previous studies indicate that patients with advanced cancer have an immunologic defect manifested by their inability to reject homotransplants of tissue-cultured cell lines as rapidly as healthy controls ...". The first publication cited in support of this statement is: Homotransplantation of human cell lines, Chester M Southam, Alice E Moore, Cornelius P Rhoads, Science 1957(Jan 25); 125(3239): 158-60 [PDF Extract][PubMed Citation (with the authors listed in a different order)]. Excerpt from the full text:

All recipients were volunteers who were aware of the general purposes of the study and the nature of the implanted materials and who were agreeable to subsequent biopsies ...

It should be emphasized that the standards for informed consent, and the procedures used for obtaining informed consent, were very different in 1957 in comparison with those used now.

An article about these latter experiments was published in Time magazine: Cancer Volunteers (Feb. 25, 1957). The first paragraph on the first page:

On wooden benches in the well-guarded recreation hall of the Ohio Penitentiary at Columbus sat 53 convicts—killers in for life, bank robbers, embezzlers, check forgers. Some wore the white jacket and trousers of hospital attendants (duty for which they had volunteered in the prison); others, fresh from work gangs, wore blue dungarees. As a man's name was called he walked upstairs to a room equipped as an emergency surgery, sat down and proffered a bare forearm. Dr. Chester M. Southam of Manhattan's Sloan-Kettering Institute then proceeded to inject live cancer cells.

The last paragraph on the first page:

The blobs of fluid containing the cancer cells made little bumps on each man's arm. In a matter of hours or days, some of these swelled up and became tender and inflamed; the healthy body's natural defenses were at work and plain to see. In other cases the men felt no appreciable discomfort, and the swelling disappeared without any noticeable inflammatory stage; the body's defenses had worked just as effectively but less conspicuously.

What have we learned during the 5 decades that have gone by since these studies were done? A lot about the ethics of human experimentation. A lot about how to avoid rejection, by the recipients, of transplanted cells obtained from unrelated donors. Quite a lot about tumor immunology and other aspects of tumor-host interactions. But, not enough (yet) about bioassays designed to detect, enumerate and characterize human CSC.