Issues & Insights

Many aspects of our current paradigm regarding cancer prevention originated at a time when most cancers were regarded as more or less homogenous collections of transformed cells. Today, it is worth reconsidering many of our commonly used preventive approaches in view of recent insights into the heterogeneous nature of many solid tumors, and the key role played by cancer stem cells.

Solid tumors are now regarded by many as aberrantly differentiated organs, sustained by small numbers of cancer stem cells, which constitute perhaps 1 in 10,000 of the total cellular mass of tumors. This notion, originally proposed and substantiated for certain types of leukemia, has recently been given support in the context of solid tumors by the isolation from human breast and brain cancers of cell subpopulations containing cancer stem cells that are able to grow in soft agar and form tumors in nude mice (1, 2) while the non-stem cell populations cannot. The cancer stem cell theory has important implications with respect to treatment, since many chemotherapy regimens are able to shrink tumors by killing non-stem cells but are unable to eradicate cancer stem cells (3), and thus have a limited impact on long-term survival.

For over 150 years, the research community has generally assumed that epithelial malignancies or carcinomas arise from epithelial cells, as originally proposed by Waldeyer, with little consideration given to other possibilities. In recent years, this epithelial model of cancer has raised for consideration the epithelial stem cell as a primary candidate for the precursor of cancer stem cells. Stem cells have generally been thought to possess unique properties of longevity, self-renewal and pluripotentiality. Adult stem cells, both circulating and organ-based, are assumed to be pluripotent – giving rise to a few but not all cell lineages – rather than multipotent, a property thought exclusive to embryonic stem cells. Adult stem cells can be tissue based, but recently much attention has been given to circulating adult stem cells, which include hematopoietic stem cells (HSCs), mesenchymal stem cells (MSCs), and multipotent adult progenitor cells (MAPCs), which have been loosely grouped together as bone marrow-derived stem cells or BMDCs.

In recent years, our view of early cancer formation has undergone a remarkable change that has shifted the focus away from the epithelial stem cell as the primary culprit. First, we now recognize that many aspects of stem cell behavior are governed not by the stem cell itself but by surrounding stromal cells, known as the stem cell niche. Secondly, a key step in tumor progression is the process of angiogenesis, which involves the recruitment of endothelial progenitor cells (EPCs) from the circulation to generate new blood vessel formation. Finally, several studies now suggest that in some model systems, solid tumors may arise not from epithelial stem cells but from BMDCs that are recruited to the site by chronic inflammation and tissue injury.

The association between inflammation and cancer has been recognized for hundreds of years, but only recently have we come to appreciate mechanistically how inflammation is able to promote and even induce cancer. A number of studies have now demonstrated that macrophages and T cells are important in sustaining tumor progression. In addition, work from several laboratories has shown that chronic inflammation leads to the mobilization of BMDCs, which can then be recruited to the sites of chronic injury. When recruited to the stomach, for example, BMDCs take on the appearance of epithelial cells, losing hematopoietic markers and in their place expressing epithelial genes [Houghton J 2004]. In this context, the BMDCs serve as a second line of defense to aid the healing process, but in the setting of a “wound that will not heal”, the BMDC may end up replacing the tissue stem cell and can then progress to malignancy. This discovery of BMDCs giving rise to epithelial tumors was made using a Helicobacter-dependent mouse model of gastric cancer. (4) Indeed, the discovery that a bacterial pathogen, Helicobacter pylori, was responsible for the chronic inflammation that can lead to both peptic ulcer disease as well as gastric cancer, was made by two Australians, Barry Marshall and J. Robin Warren, who recently received the 2005 Nobel Prize for Medicine for their discoveries.

The recognition that circulating BMDCs can engraft in epithelial tissues, take on many of the characteristics of epithelial cells and then give rise to solid tumors, offers a new and different perspective on the process of carcinogenesis. (5) Many of the former “black box” aspects of cancer become somewhat easier to explain. The notion of a “field effect”, whereby cancer arises in a field of normal appearing but genetically abnormal cells, becomes understandable if one assumes widespread engraftment by BMDCs. If we assume that BMDCs have intrinsic differences in their overall program of gene expression, the fact that epigenetic changes occur earlier in cancer than genetic changes, makes a bit more sense. The metastatic nature of cancer could also be viewed more as an inherent property of cancer stem cells derived from BMDCs, rather than as something necessarily acquired after multiple genetic hits. Most important, though, is that in the BMDC model, cancer initiation is not due simply to a genetic mutation but to the initial process of engraftment of BMDCs in the damaged epithelium.

How then could chemoprevention work, and how should we be developing newer chemopreventive agents? And could there be a way to predict which patients are most at risk for cancer based on this new model? If the engraftment of a BMDC clone in a damaged or inflamed tissue is a very early step on the long road to cancer, then therapies that might restrain this engraftment process or alter the early differentiation programming of the stem cells, would likely serve as effective chemopreventive agents. In addition, patients at risk also may be those individuals who have mobilized their bone marrow stem cells into the circulation. This mobilization of stem cells could be due either to well-known carcinogens or to a genetic predisposition.

Many of the factors currently known to regulate BMDCs are cytokines and chemokines. Interleukin-1 beta is one such factor, and patients with high-expressing IL-1beta genotypes are at increased risk for developing gastric cancer. Greater attention should be given to modulation of the stem cell niche; stem cells are by nature slowly cycling cells, which serves to protect the integrity of their DNA, but alterations in the stem cell niche can lead to rapid cycling and possibly lead to gradual conversion of normal stem cells into cancer stem cells. Alterations in the niche—such as upregulation of metalloproteinases, prostaglandins, or adhesion molecules—could be induced by environmental carcinogens or by cytokines, and this may be the first step toward neoplasia. How known carcinogens, such as tobacco, interact with the stem cells and the stem cell niches and influence their behavior deserves the next level of our research attention. Further understanding of the nature and behavior of stem cells may offer many new strategies for inhibiting cancer formation or carcinogenesis at its earliest stages when it may be most controllable.

References

1. Al-Hajj M, Wicha MS, Benito-Hernandez A, et al. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA. 2003;100:3983-3988.
2. Singh SK, Hawkins C, Clarke ID, et al. Identification of human brain tumour initiating cells. Nature. 2004;432:396-401.
3. Reya T, Morrison SJ, Clarke MF, et al. Stem cells, cancer, and cancer stem cells. Nature. 2001;414:105-111. Review.
4. Houghton J, Stoicov C, Nomura S, et al. Gastric cancer originating from bone marrow-derived cells. Science. 2004;306:1568-1571.
5. Houghton J, Wang TC. Helicobacter pylori and gastric cancer: a new paradigm for inflammation-associated epithelial cancers. Gastroenterology. 2005;128:1567-1578. Review.