One theory of cancer that has great importance is the concept of the cancer stem cell (CSC).

A consensus panel of the American Association for Cancer Research (AACR) has defined the CSC as “a cell within a tumor that possesses the capacity to self-renew and to give rise to the heterogeneous lineages of cancer cells that comprise the tumor.”

• (http://stemcells.nih.gov/info/Regenerative_Medicine/pages/2006chapter9.aspx)

According to a systematic review, a tumor contains different populations of cells. CSCs are a small subset of relatively peaceful-seeming cells in the tumor that have the ability to suddenly self-renew and produce an array of non-stem “daughter cells” that make up the bulk of the tumor. The latter cells are also called “bulk cells.”

Something like this was postulated by some of the great pathologists of the 19th century. Rudolf Virchow and his student, Julius F. Cohnheim, proposed that cancer originated from “dormant embryonic-like cells present in mature tissue.”

• (Enrique Grande y Luis Antón Aparicio, editores. Stem Cells in Cancer: Should We Believe or Not? Dordrecht: Springer, 2014, p. vi.)

Trophoblastic Theory of Cancer

The similarity of cancer to tissues contained in a normal embryo was commonplace in late 19th-century science. A clue as to the embryonic nature of cancer was the rare but well-established occurrence of teratomas, which are tumors containing a jumbled assortment of tissues, occurring at the wrong time and place. According to the Cleveland Clinic website:

• “A teratoma is a rare type of germ cell tumor that may contain immature or fully formed tissue, including teeth, hair, bone, and muscle. Teratomas may be cancerous or noncancerous, and they can affect people of all ages. Treatment involves surgical removal. Cancerous teratomas may require chemotherapy, radiation therapy or other cancer treatments.”

Another precursor of the modern understanding of cancer stem cells was the “trophoblastic theory of cancer,” proposed by the English scientist John Beard, DSc. Beard for decades taught comparative embryology at the University of Edinburgh, Scotland. In the latter half of his career, he devised a theory that all cancer was essentially trophoblastic tissue. This is normally a key characteristic of pregnancy. Beard even published a book on this topic, The Enzyme Treatment of Cancer, but it failed to gain any traction in medical circles. He himself died in obscurity in 1924 and his theory was quickly forgotten.

By a circuitous route, however, Beard’s work later was revived and became an element in the laetrile controversy. Laetrile proponents claimed that the natural control of embryo-like cells (identified with the trophoblasts of pregnancy) were pancreatic digestive enzymes, particularly trypsin and chymotrypsin. This theory was also popularized by William Donald Kelley, Nicholas Gonzalez, MD, of New York, both deceased, and by Linda Isaacs, MD, now practicing in Austin, Texas.

The concept of cancer arising from a primitive precursor cell was further defined in 1959 by Sajiro Makino (1906-1983), who introduced the term “tumor stem cells.” Makino was born in Chiba, Japan, in 1906, graduated from Hokkaido University (1930), and studied in the United States in 1951.  He was a long-time professor at the University of Hokkaido, Japan, and won various scientific awards during his time.

Makino defined CSCs, in the 1950s, as a subpopulation of cells “that were insensitive to chemotherapy and had chromosomal features different from the bulk of cells.” His research wasn’t welcome news to oncologists who were just then gearing up to use “drastic” chemotherapy (Makino’s word) to a widening circle of patients. In more than half a century since its initial publication, his pioneering article has only been cited 14 times, or about once every five years!

• (Makino S. The role of tumor stem-cells in regrowth of the tumor following drastic applications. Acta Unio Int Contra Cancrum. 1959;15(Suppl 1):196-8. PMID: 14420161, emphasis added)

Cancer stem cells are also known as tumor-initiating cells, and are defined as “rare cells with indefinite potential for self-renewal that drive tumor formation.” Some people identify these with “circulating tumor cells” (CTCs), or “circulating tumor stem cells,” although that is not certain.

• (Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001 Nov 1;414(6859):105-11. doi: 10.1038/35102167. PMID: 11689955)

While chemotherapy and radiation therapy may harm or kill ordinary cancer cells, CSCs are resistant to radiation and chemotherapy. Yet they may, in fact, be the ultimate source of tumor recurrences and metastases (Hanahan and Weinberg’s cancer hallmark #6). This is the most ominous aspect of cancer—the one that in effect makes cancer cancerous.

• (Lapidot T, Sirard C, Vormoor J, et al. A cell initiating human acute myeloid leukemia after transplantation into SCID mice. Nature. 1994 Feb 17;367(6464):645-8. doi: 10.1038/367645a0. PMID: 7509044; Huntly BJ, Gilliland DG. Leukemia stem cells and the evolution of cancer-stem-cell research. Nat Rev Cancer. 2005 Apr;5(4):311-21. doi: 10.1038/nrc1592. PMID: 15803157)

Characteristics of Cancer Stem Cells

The four key characteristics of CSCs are as follows:

1.  “Stemness,” the capacity to self-renew and to turn into various kinds of tumor cells
2.  Abnormal signaling pathways within the CSC and from cell to cell
3.  Resistance to conventional therapies, including radiation and chemotherapy
4.  Contributing to (or causing) tumor recurrences and metastases

According to a University of California, Los Angeles (UCLA) review:

• “The cancer stem cell hypothesis…is a hierarchical model which states that only a subset of cells within a tumor, the CSC, are capable of initiating and propagating [cancer] due to their increased proliferative capacity.”
• (Vira D, Basak SK, Veena MS, et al Cancer stem cells, microRNAs, and therapeutic strategies including natural products. Cancer Metastasis Rev. 2012 Dec;31(3-4):733-51. doi: 10.1007/s10555-012-9382-8. PMID: 22752409)

In other words, this subset of cells, successfully hiding within a much larger population of “daughter” cells, are truly dangerous. They are the “sleeper cells” of the body. What is more, chemotherapy and radiation not only do not kill CSCs well but may actually introduce “stemness” into what were originally non-stem cancer cells!

Recurrence of Cured Cancer

This explains why apparently cured cancers can quickly recur and overwhelm the host. According to University of Central Florida scientists, the CSC theory explains:

• “…why complete initial responses to treatment rarely lead to cures. The initial responses mirror the therapeutic effect on the cells that form the tumor bulk while leaving behind CSCs that are responsible for relapse, the real threat to tumor cell eradication.”

This also explains why chemotherapy and radiation therapy, which are apparently effective and can shrink tumors, can also, under certain circumstances, be unable to deal with the most malignant portion of the tumor.

Can Chemotherapy make tumors more malignant?

There is laboratory evidence that chemotherapy may in fact make some tumors more malignant. At the University of Massachusetts, Amherst, and Harvard Medical School, Boston, they studied cancer stem cells in fruit flies. (Strangely, stem cells in the gut of fruit flies are similar to those in the gut of humans). The authors found that some FDA-approved chemotherapy drugs could promote the growth of CSCs:

• “These results reveal an unanticipated side effect on stem cells that may contribute to tumor recurrence. This side effect could contribute to refueling the growth of the very tumors that these chemotherapeutics are intended to inhibit.”
• (Markstein M, Dettorre S, Cho J, et al. Systematic screen of chemotherapeutics in Drosophila stem cell tumors. Proc Natl Acad Sci U S A. 2014 Mar 25;111(12):4530-5. doi: 10.1073/pnas.1401160111. Epub 2014 Mar 10. PMID: 24616500; PMCID: PMC3970492)

A chilling statement! But what is the solution to this dilemma? According to the authors,

• “Supplementing traditional chemotherapeutics with anti- inflammatories may reduce tumor recurrence.”

Anti-inflammatories could also be food supplements such as curcumin, resveratrol or sulforaphane. These phytonutrients could be effective at preventing the negative effects of chemotherapy, in this case by preventing anti-cancer drugs from promoting the growth of CSCs and thus making a bad situation worse.

This is not a reason to avoid difficult, but effective, treatments when they are necessary, such as chemotherapy for pediatric leukemia. But it is a recognition that sometimes well-intended actions produce unintended consequences.

It is simplistic to think that cancer stem cells are entirely different from ordinary cancer cells. In fact, they interact with those cells in complex ways:

• “Cancer cells and stem cells are like mirror images of each other. There appears to be malignant potential in every stem cell and stem cell potential in malignant cells.”
• (Fehmi Narter. Re: Cancer: A ‘Stem-Cell” Disease. J Urol Surg 2015; 2: 207-207)

According to German scientists:

• “Interestingly, an equilibrium seems to exist between CSCs and non-stem cancer cells, and there are indications that CSCs can be recruited from non-stem cancer cells. As a consequence, it may be necessary to combine a therapy targeting CSCs with common chemotherapy that targets the bulk tumor to avoid the regeneration of CSCs.”
• (Dittmer J, Rody A. Cancer stem cells in breast cancer. Histol Histopathol. 2013;28(7):827–838)

Within conventional medicine, talk of cancer stem cells died out for most of the 20th century. The modern era began in 1994 when an Israeli scientist, Tsvee Lapidot, Ph.D., then at the Hospital for Sick Children, Toronto, provided the first solid evidence for the existence of CSCs in acute myeloid leukemia (AML).

Lapidot isolated a single CSC among 250,000 normal blood cells! These cells were relatively immature and thus had more “stemness” to them, i.e., they were closer to primitive blood-forming stem cells than to mature blood cells. Yet, amazingly, these special cells, when they were injected into mice with compromised immune systems, could on their own initiate AML.

• (Lapidot, T., C. Sirard, J. Vormoor, B. et al. “A Cell Initiating Human Acute Myeloid Leukaemia after Transplantation into SCID Mice.” Nature 367, no. 6464 (February 17, 1994): 645–48; Welcome letter | Tsvee Lapidot Lab)

In 2001, Nature published its first article on CSCs, “Stem cells, cancer, and cancer stem cells” by Stanford researchers. This created a sensation and has been cited in over 1,800 other journal articles. Now over 1,700 such papers appear every year! CSCs have now been identified in breast, brain, colon, head & neck, liver, lung, pancreatic, and prostate cancers, as well as multiple myeloma and leukemia.

Cancer stem cells have now been identified in breast, brain, colon, head and neck, liver, lung, pancreatic, and prostate cancers, as well as multiple myeloma and leukemia.

• (Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001 Nov 1;414(6859):105-11. doi: 10.1038/35102167. PMID: 11689955)

But the picture is anything but simple. There is no single CSC and the stem cells of each of the the above-mentioned tumors turn out to have slightly different cell surface markers. There are currently about 40 cell surface markers of cancer stem cells.

• (Kim WT, Ryu CJ. Cancer stem cell surface markers on normal stem cells. BMB Rep. 2017;50(6):285-298. doi:10.5483/bmbrep.2017.50.6.039)

Patients classified the old-fashioned way, i.e., by having cancers in the same anatomical location, often turn out to have different types of CSCs. These markers may also change over time. So it may be impossible to come up with a single drug that successfully targets all CSCs per se. Current thinking is that one will also need to give some other agents (chemotherapy or immunotherapy) to completely eradicate tumors.

However, a few leading candidate drugs (and some very promising natural agents) have emerged from laboratories around the world.

Controlling CSCs is among the promising topics in cancer research today.