Cancer stem cells: a model in the making

Cancer stem cells and their potential roles in tumor heterogeneity are currently subjects of intense investigation. Studies suggest that these cells may develop from any normal cell and have begun to elucidate their molecular profiles. The percentage of a tumor composed of cancer stem cells varies greatly, and researchers believe that multiple types of these cells may exist in a single neoplasm. Cancer stem cells may be formed by epithelial–mesenchymal transition and seem to be less prevalent in metastases than in corresponding primary tumors. These cells appear to have therapeutic sensitivities different from those of cancer cells with more differentiated features. Looking into the many questions that remain about the cancer stem cells model might lead to more effective cancer prevention, diagnosis, and treatment.

Introduction

Decades of scientific research and clinical observations have revealed much about cancer [1, 2, 3]. This disease originates when a single cell accumulates multiple mutations that together drive uncontrolled proliferation, resistance to apoptosis, and other hallmarks of malignancy. Cancer cells in resultant tumors undergo additional genetic or epigenetic changes and interact with their individual microenvironments, leading to a constantly changing variety of tumor cell types within a single neoplasm. This shifting in intra-tumoral heterogeneity, which has been proposed to also be due to the continuous selection of dominant clones [4] and the differentiation of malignant stem cells [5], underlies tumor progression and resistance to treatment and results in inter-tumoral heterogeneity. On the basis of their overall nature, tumors can be classified by organ of origin, tissue type, phenotypic subtype, and stage of progression. Knowledge of the characteristics of cancer has led to improved survival of patients, but many currently used therapies have detrimental side effects, and mortality rates are still high because of metastasis and recurrence. Therefore, a more complete understanding of cancer is needed.

Recently, the study of ‘cancer stem cells’ has become a popular area of cancer research, as shown by increasing numbers of articles and patents related to this field in the past few years (Table 1). By definition, cancer stem cells are a subset of cancer cells with the stem-cell-like ability to produce all cancer cell types found in a tumor, which may include cells with more differentiated features [6]. They are not necessarily derived from normal stem cells, and it is unclear whether they always have the ability to differentiate or other normal stem cell characteristics. Thus, the “cancer stem cell” name is more of a reflection of stem-cell-like phenotype than of true stemness. The idea that transformed stem cells are the root of cancer was proposed over a century ago [7], but cancer stem cells were not first identified until 1994 when researchers found that a purified acute myeloid leukemia cell population expressing particular cell surface markers could efficiently form tumors when injected into mice while other cell populations from the same cancer sample could not [8]. Since then, using this assay, cancer stem cells have been identified in tumors from many organs, including breast, brain, prostate, pancreas, head and neck, colon, lung, skin, liver, and ovary [9, 10, 11, 12, 13, 14, 15, 16, 17, 18•].

Owing to their ability to initiate tumors, cancer stem cells are proposed to play roles in oncogenesis, tumor growth, metastasis, and cancer recurrence. The goal of this review is to explain why and how cancer stem cells are currently thought to be involved in each of these tumorigenic processes, focusing primarily on results from the past two years.