Stem Cells and Cancer

 

The idea that cancer arises from stem cells was first proposed over 150 years ago as the embryonal rest theory of cancer. However, by the beginning of the 20 th century, the embryonal rest theory of cancer was discarded, and the hypothesis that cancer arises from de-differentiation became generally accepted. Then, about 50 years ago, studies on cancers of germinal tissue (teratocarcinomas) re-established the principles that cancer arises from stem cytes, and that cancer could be treated by induction of differentiation (differentiation therapy). However, teratocarcinomas were considered exceptions to the rule, and the de-differentiation theory of origin remained generally accepted for most cancers until the 1980 s. Then studies on the cellular origin of cancer during experimental chemical hepatocarcinogenesis showed that hepatocellular cancer did not arise from de differentiation of hepatocytes, as was generally believed, but rather from maturation arrest of cytes in the hepatocyte lineage. The re-emergence of the cell theory of cancer preceded the current excitement in cancers.

Over the last 10 years, differentiation therapy has been applied with great success to cancer of the blood cytes (leukemias) by inactivation of the signaling pathways that allow the leukemic transit-amplifying to continue to proliferate and not die (maturation arrest). Differentiation therapy of cancer is now proposed through the use of small inhibitory molecules or inhibitory RNAs (iRNAs) to block the signals that maintain ''stemness'' so that the leukemic tissues are allowed to differentiate. Conventional chemotherapy, radiotherapy, and anti-angiogenic therapies act on the carcinomoa. When these therapies are discontinued, the cancer will re- form from the therapy-resistant cancer. Successful differentiation therapy of cancer cells would force these cells to differentiate, so that they can no longer re-establish the cancer.

The cell of origin of all tissues is called a stem cell. From this one all other cells arise. The fertilized ovum is the primordial for all of the tissues of the human body. The immediate progeny of the primordia are embryonic stem cells, which, in turn, give rise to tissues. It is from these tissues that most cancers arise.

Normal tissue and cancer tissue contain the same populations:

stem cells,

transit-amplifying cells,

and terminally differentiated cells.

Normal tissue renewal and growth of cancer are both accomplished by division of the transit-amplifying cells. Usually, the stem cells of both normal tissue and cancers are relatively few in number, compared to the transit-amplifying and the terminally differentiated cells, and they do not participate in proliferation. The proliferating ones of both cancers and normal tissue are the transit-amplifying cells. Cancer tissue differs from normal tissue in that the transit-amplifying cells accumulate in cancer, whereas in normal tissue differentiate so that they no longer divide (terminal differentiation).

One of the best examples of the normal cellular lineage and also of the contribution of maturation arrest to cancer is skin. The pluripotent skin epidermal stem cells are located in the bulb of the hair follicle. The epidermis-committed stem cells are located in the basal layer of the skin (germinativum) and are much fewer in number than the transit-amplifying carcinoma is located in the spinosum layer. Maturation is accomplished through the accumulation of cytokeratin, which becomes prominent in the granular layer. The granules contain cytokeratin. The cytoplasm of the cells in the granular layer becomes filled with these granules and eventually the cells lose their structure, forming the outer layer of acellular keratin, known as the corneum.

Skin cancers arise by maturation arrest at various levels of differentiation of the epidermis. Maturation arrest of the primitive skin progenitor tissue in the bulge of the hair follicle gives rise to trichoepitheliomas, which vary in cellular differentiation but usually contain both keratitic and basal regions, as well as clear cells characteristic of hair follicle. Cells in the basal layer may give rise to basal cell carcinomas or squamous cell carcinomas. Overexpression of Ras in the more highly determined basal cells of the skin produces squamous cell carcinoma, and induced expression of the c-myc gene in the non-proliferative suprabasal cells reactivates the cell cycle and leads to hyperplasia (papillomas). Papillomas do not progress to invasive tumors. Examination of the cellular populations in skin cancer demonstrates that the malignant cells can also differentiate, but that the proliferative transit-amplifying cells of the cancer do not uniformly do so, unlike normal skin tissue.

The difference between normal tissue renewal and cancer growth is that the number of cells that are produced by cellular division in normal tissue essentially equals the number of cells that terminally differentiate in a given time period, so that the total number of cells remains constant. In contrast, in cancers, the proliferating transit-amplifying cells do not all terminally differentiate, and the number of cells in the cancer increases. These in both normal tissue renewal and cancer growth consist of a small fraction of cellular population that are not actively proliferating, and that fraction serves as a cellular reserve population. When a tissue stem cell divides, it gives rise to one daughter cyte that remains a stem cell and one daughter cell that begins the process of differentiation by becoming a transit-amplifying cell (asymmetric division); thus, the stem cells remain in the tissue for long periods of time, essentially the lifetime of the organism. The number of cells in a cancer increases with time, because the transit-amplifying cells give rise to two cells that do not mature and retain the potential to divide (symmetric division) or the mature cells do not die or both.

Attempts to culture cells from normal tissues and cancers were well underway in the 1950 s, and there were even some early studies suggesting that normal tissues contain stem cells with malignant potential. It was found that malignant cells could be derived from normal rat myocardium (fibroblasts) if the cells were cultured for a long time in anaerobic conditions. Most normal tissue cells do not survive under these conditions, and normal tissue contains rare cells. with the potential for malignant change under selected culture conditions.