During the past several decades, the existence of a group of cells possessing stem cell–like properties within the heterogeneous makeup of a tumor has been cemented and their potential role in all aspects of cancer development and progression has been uncovered. These so-called cancer stem cells (CSCs) comprise only a tiny portion of the tumor, yet they could prove to be the most important therapeutic targets in a broad range of tumor types.
Drugs that target CSCs directly are now emerging. Particular progress has been made in the development of small-molecule inhibitors of key signaling pathways that are responsible for the unique characteristics of stem cells, developed by biotechnology companies focused solely on CSC-targeting therapies.
The lead candidate in this area, BBI608, is undergoing phase III testing in gastric and gastroesophageal junction (GEJ) cancers.
Seed and Soil Theory
The long-accepted paradigm of cancer development has been that normal cells are transformed into malignant ones through the accumulation of genetic alterations in hallmark cellular processes. Identification of the molecular drivers underlying this transformation sparked a revolution in cancer therapy with the development of targeted drugs.
Despite significant promise, targeted therapies have not proved to be the “magic bullet” they were initially hailed to be. Therapeutic resistance and tumor recurrence remain significant unmet challenges, and metastatic disease is responsible for more than 90% of cancer-related deaths.
In an effort to tackle metastatic disease, researchers have been revisiting several historical theories and placing them into a modern context in cancer cell biology.
More than 150 years ago, the German pathologist Rudolf Virchow observed similarities between tumor tissue and embryonic tissue and suggested that tumors arise from the activation of embryo-like stem cells.
A few decades later, Stephen Paget postulated his seed and soil theory—that tumor metastases require a favorable interaction between the metastatic tumor cells (the seed) and their organ microenvironment (the soil).
These two concepts have been refined and married in a burgeoning field of cancer research, with the suggestion that Paget’s “seeds” are, in fact, Virchow’s “cancer stem cells.”
Cancer Stem Cells in Microenvironment
The complex role of cancer stem cells in the tumor microenvironment is believed to include self-renewal capabilities that help initiate and maintain the formation of the environment itself and promote cancer progression.
Schiavoni G, Gabriele L, Mattei F. The tumor microenvironment: a pitch for multiple players [published online April 17, 2013]. Front Oncol. 2013;3:90. doi: 10.3389/fonc.2013.00090. eCollection.
The first solid evidence of the existence of CSCs came from patients with leukemia in the 1990s. Since then, CSCs have been identified in most types of human cancer, including both solid tumors and hematologic malignancies, and have generated intense skepticism and unfettered enthusiasm in equal measure.
Undoubtedly, the existence of CSCs has profound prognostic and therapeutic implications and is changing our fundamental understanding of cancer. Mounting evidence suggests CSCs are responsible for all of the important characteristics of tumors, from initiation to metastasis.
Furthermore, because these cells are typically dormant, they are resistant to traditional therapies that target rapidly proliferating cancer cells. It is suggested that the CSCs that are left behind after treatment drive the eventual recurrence observed in almost all patients with cancer. From there it is only a small leap to suggest that eliminating CSCs could be the elusive “cure” for which cancer researchers are searching. However, although initial skepticism about the existence of CSCs has been overcome, many leading researchers remain cautious about overstating the potential of the therapeutic targeting of these cells. Indeed, CSC research presents technical challenges and many unanswered questions.
What are CSCs?
Even the definition of CSCs has proved challenging, but essentially they represent the tiny fraction of cells within a tumor that are capable of giving rise to new tumors. They were dubbed stem cells because of the parallels that can be drawn with normal stem cells, in their unique potential to develop (differentiate) into any other cell type within the tumor.