Stem cells and cancer: An introduction

Abstract

Cancer tissue contains the same cell populations as do normal adult tissues: stem cells, proliferating transit-amplifying cells, terminally differentiated (mature cells) and dead cells. However, the cancer transit-amplifying cells are arrested at a stage of maturation where many of the transit-amplifying cells continue to divide and do not die. During normal tissue renewal, the transit-amplifying cells produce progeny that differentiate and die. Because of this difference, cells in a cancer continue to accumulate. On the other hand, the number of dividing cells in normal tissue essentially equals the number of differentiating cells, so that the total number of cells remains relatively constant. 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 cells (teratocarcinomas) re-established the principles that cancer arises from stem cells, that cancers contain stem cells, 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 cell in the hepatocyte lineage. The re-emergence of the stem cell theory of cancer preceded the current excitement in cancer stem cells. Over the last 10 years, differentiation therapy has been applied with great success to cancer of the blood cells (leukemias) by inactivation of the signaling pathways that allow the leukemic transit-amplifying cells to continue to proliferate and not die (maturation arrest). Differentiation therapy of cancer stem cells 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 stem cells are allowed to differentiate. Conventional chemotherapy, radiotherapy, and anti-angiogenic therapies act on the cancer transit-amplifying cells. When these therapies are discontinued, the cancer will re-form from the therapy-resistant cancer stem cells. Successful differentiation therapy of cancer stem cells would force these cells to differentiate, so that they can no longer re-establish the cancer. © Springer Science+Business Media, LLC 2009. All rights reserved.