Cancer Metastasis and Cancer Stem Cell/Niche

Parallels drawn between stem cells and cancer are not new. However, these shared features are becoming increasingly important as our understanding of disseminated, recurrent and metastatic cancer cell biology continues to develop. Indeed, nearly all cancer-related deaths are the result of recurrent and metastatic disease, highlighting the need for a more comprehensive schema of how tumors colonize new sites, resist therapy and evolve. In this chapter, we compare the phenotypes of stem cells, cancer stem cells (CSCs) and metastatic cells, highlighting notable points of contrast. We begin with an introduction to stem cell biology, tumorinitiating CSCs, metastatic cells and discuss shared features. The implication of the stem-like phenotype extends to many characteristics of cell biology: cell division, differentiation, morphology, gene expression, motility, invasion, clonogenicity, capacity for colonization, metabolism and the interaction of these cells with their surrounding microenvironment. Stem cell phenotypes are highly complex and, while there may be a number of shared features, there are important elements that are uniquely tissue-dependent. While staunch definitions based upon a single biomarker of stemness have proven inadequate in broader applications, seeing universal themes of the stem cell phenotype will provide critical insights for studying cancer. Our understanding of this complex biology is critical for developing rational and dynamic therapeutic interventions for patients with recurrent and metastatic cancer.

Cell surface glycans are recognized to be good markers for human pluripotent embryonic stem cells. Typical glycan markers for human embryonic stem cells include SSEA-3, SSEA-4, TRA-1-60 and SSEA-5. Some of these glycans are recently known to be frequently expressed in human cancers, especially in cancer stem cells. Cell surface glycans undergo drastic changes also during malignant transformation, and the glycans which preferentially appear in cancers are clinically utilized as diagnostic markers for human cancers. Such tumor marker glycans include sialyl Lewis A and sialyl Lewis X, expression of which we recently showed to be enhanced in cancer stem-like cells that had undergone epithelial-mesenchymal transition. Sialyl Lewis A was also shown to be expressed in human embryonic stem cells, and to behave as an embryonic stem cell specific marker. Thus, a glycan initially described as a cancer-associated glycan in the cancer research field is now known to be an embryonic stem cell marker, while glycans formerly regarded to be typical embryonic stem cell markers in the embryology field are now shown to be cancer stem cell markers. This suggests the presence of a common induction mechanism for these glycans shared by embryonic stem cells and cancer stem cells. However, the regulatory mechanisms for stem-cell specific glycan expression remain largely unknown. In this chapter we will introduce how glycan-related genes responsible for synthesis of the stem-cell specific glycans are regulated through specific epigenetic modification, by niche-associated microenvironmental factors such as hypoxia, and during a morphogenic process like epithelial-mesenchymal transition.

Tumor growth and metastasis are facilitated by the formation of new blood vessels, a process known as angiogenesis. The blood vessels formed around the tumor supply it with oxygen and nutrients, which together support its progression. Moreover, the newly formed blood vessels serve as channels through which tumor cells metastasize to distant organs. Tumor blood vessels, and especially the endothelial cells lining tumor blood vessels (tumor endothelial cells, TECs), have therefore gained interest as targets in cancer therapy. Although newly formed tumor blood vessels originate from pre-existing, normal vessels, they have a distinctively abnormal phenotype, including important morphological alterations. The balance between the angiogenic stimulators and inhibitors regulates angiogenesis in the tumor microenvironment. Furthermore, TECs constitute a heterogeneous population, exhibiting characteristics induced largely by tumor microenvironmental factors. In this chapter we review recent studies on TEC abnormalities regarding to cancer progression and consider the therapeutic implications thereof.

Cancer metastasis is one of the most crucial problems in the field of medical research. There are two types of approaches to find a new way to treat cancer metastasis; Targeting cancer stem cells, or stromal cells in the premetastatic phase. Interactions between these two elements synergistically enhance the survival of metastatic cancer cells and promote their re-growth in the distant organ. In this review, first we summarize the recent trends in cancer stem cell studies. Then, we discuss the premetastatic phase, based on our investigations. We also review various types of tumor-associated stromal cells (monocyte/macrophage, fibroblast, adipocyte, dendritic cell, neutrophil, and natural killer cell) in relations with the tumor microenvironment formation. Moreover, dormant tumor cells and circulating tumor cells are included in this review.

The cancer stem cell (CSC) theory has emerged as an attractive hypothesis for tumor development and progression including metastasis. The theory suggests that tumors consist of subsets of cells with functional heterogeneity in which one small subset has the characteristics of stem cells. These stem cells have the capacity of both self-renewal and heterogeneous differentiation into cancer cells that comprise the tumor. They can also play an important role in invasion, metastasis and, finally, recurrence. Based on the pathgenesis of the cancer metastasis, the recurrences after curative surgery probably develop from the proliferation of occult micro-metastases already established at the time of surgery. The attractive ideas about CSCs hypothesis in metastasis can partially explain the concept of minimal residual disease like occult micro-metastases after curative resections. CSC hypothesis in clinical metastasis is now giving a deep impact on surgical oncology. Efforts to develop diagnostic and therapeutic approach with the successful results from CSC studies would lead to impressive improvement for cancer patients in surgery.