Paradigm Shift: Target the cancer STEM cells

Dr. Weeks’ Comment: Dr Wicha is a pioneer in human oncology.

Cancer Stem Cells: An Old Idea—A Paradigm Shift

Max S. Wicha, Suling Liu and Gabriela Dontu

Published in Cancer Research – SOURCE


Although the concept that cancers arise from “stem cells” or “germ cells” was first proposed about 150 years ago, it is only recently that advances in stem cell biology have given new impetus to the “cancer stem cell hypothesis.” Two important related concepts of this hypothesis are that (a) tumors originate in either tissue stem cells or their immediate progeny through dysregulation of the normally tightly regulated process of self-renewal. As a result of this, (b) tumors contain a cellular subcomponent that retains key stem cell properties. These properties include self-renewal, which drives tumorigenesis, and differentiation albeit aberrant that contributes to cellular heterogeneity. Recent experimental evidence in a variety of tumors has lent strong support to the cancer stem cell hypothesis that represents a paradigm shift in our understanding of carcinogenesis and tumor cell biology. This hypothesis has fundamental implications for cancer risk assessment, early detection, prognostication, and prevention. Furthermore, the current development of cancer therapeutics based on tumor regression may have produced agents that kill differentiated tumor cells while sparing the rare cancer stem cell population. The development of more effective cancer therapies may thus require targeting this important cell population. (Cancer Res 2006; 66(4): 1883-90)


In a thought-provoking article published in Fortune in 2004, Leaf, a cancer survivor, poses the question, “Are we losing the war on cancer?” ( 1). In this article, he reviews data on the progress made since the “war on cancer” was declared in 1961. Over this time, there have clearly been dramatic advances in the treatment of such diseases as childhood leukemia, Hodgkin’s disease, and testicular cancer. Furthermore, the overall mortality for some of the common epithelial malignances, such as breast cancer and prostate cancer, have been declining recently largely due to advances in early detection and prevention. However, as Leaf points out, for the four most common epithelial malignancies (lung, breast, prostate, and colon cancers), the survival of patients with metastatic disease has not changed significantly over the past several decades. Despite these statistics, there is considerable optimism in the cancer research community that new targeted therapies will significantly improve on the results of empiric-based therapeutics. The ability to specifically target pathways deranged in cancer raises the hope of developing therapies with enhanced specificity and decreased toxicity. However, as our ability to attack specific targets increases, a fundamental question remains, “Are we targeting the right cells”? Evidence is accumulating that most, if not all, malignancies are driven by “a cancer stem cell compartment.” Furthermore, these cancer stem cells may be inherently resistant to our current therapeutic approaches. The cancer stem cell hypothesis has fundamental implications for understanding the biology of carcinogenesis as well as for developing new strategies for cancer prevention as well as new therapies for advanced disease. In this commentary, we will discuss the cancer stem cell hypothesis, including recent evidence supporting its validity, and the implications of this model for cancer prevention and therapy.


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