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A 50-year-old heavy smoker was treated for small cell lung cancer, limited stage, with chemotherapy and radiation. The bulky tumor in his chest was no longer seen after the treatment, and he was told he had a complete response.

Two months following the treatment, the cancer recurred and was resistant to any further systemic therapy.

He asks during his last clinic visit before going to hospice, “How did the cancer come back so quickly, and why was it not cured when I had a complete response?”

Learning Objectives

  1. What is meant by the term cancer stem cells?

  2. How can cancer stem cells (CSCs) explain treatment resistance and recurrence of disease?

  3. What are the normal stem cells in the lung that the CSCs may be mimicking?

Lung cancer is a progressive disease arising from accumulation of genetic mutations and natural selection of the genetic clones most fit to continue proliferation. However, even within isogenic cancer cell populations, heterogeneity in phenotypes exists. For example, not every lung cancer cell can grow ex vivo in two-dimensional or three-dimensional culture,1,2 and it does not appear that every cell has an equal ability to survive chemotherapy, evade the immune system, or metastasize.3,4 As early as 1858, the idea of “stemness” in cancer was raised by the pathologist Rudolph Virchow,5 and throughout the past century the idea that tumors are driven by a population of stem-like cells has been constantly proposed as the reason for clonal tumor cell heterogeneity. In the past several decades, the idea has been formally termed the cancer stem cell hypothesis.6,7

The CSC hypothesis proposes that tumors can be hierarchically organized, and that only the cancer cells at the top of the hierarchy have the unique properties of self-renewal and the ability to differentiate into multiple lineages (Figure 8-1). In normal tissues, these traits of self-renewal and differentiation allow stem cells to repopulate organs during homeostatic turnover and after tissue injury. In the context of cancer, “stemness” implies that these cancer cells have a more unlimited proliferative potential than “nonstem” cancer cells and therefore that they are the cells able to drive tumor growth long term. Corollaries to the CSC hypothesis include that CSCs are relatively resistant to chemotherapies through multiple mechanisms, including relative quiescence; that CSCs drive recurrent disease; and that CSCs are responsible for seeding metastases.3,4,8 Whether one or all of these properties of long-term tumor growth, disease resistance to therapy, and metastatic spread of cancer can be attributed to a single subpopulation of cancer cells relies largely on the composition of the tumor, including the mutations present, the polyclonality of the tumor, and the differentiation state of the cells within the tumor.8 In order to fully appreciate the possible traits of a CSC population, it is first necessary to understand the ...

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