Metastasis is the one of the biggest challenges in cancer therapy. Here we share part of a latest article which discusses the nature of the tumor cells that give rise to metastases by Kevin J. Cheung and Andrew J. Ewald. The origin of this article is Science 08 Apr 2016: Vol. 352, Issue 6282, pp. 167-169 (DOI: 10.1126/science.aaf6546) where you can get the full article. Also Creative Biomart provides molecular tools such as recombinant proteins for tumor metastasis research applications when you need.
Abstract: Despite decades of study, there are still many unanswered questions about metastasis, the process by which a localized cancer becomes a systemic disease. One of these questions is the nature of the tumor cells that give rise to metastases. Although conventional models suggest that metastases are seeded by single cells from the primary tumor, there is growing evidence that seeding requires the collective action of tumor cells traveling together in clusters. Here, we review this evidence, which comes from analysis of both experimental models and patient samples. We present a model of metastatic dissemination that highlights the activities of clusters of tumor cells that retain and require their epithelial properties.
Metastasis is a complex, multistep process that requires cancer cells to detach from the primary tumor, migrate through adjacent tissue, access and travel through the vasculature, and then survive and proliferate in distant organs. There is an added challenge for carcinomas because the adult epithelial cells from which they arise are normally polarized and nonmotile. Metastasis therefore represents a striking divergence from their homeostatic condition. However, epithelial tissues are highly dynamic and migratory during development and tissue repair, and epithelial cells can acquire mesenchymal molecular features in both developmental and disease states.
Current therapies are not sufficiently effective in treating metastatic disease, and so it is important that we determine the cellular and molecular features of the cancer cells that “seed” new tumors in distant organs. In this Perspective, we discuss recent work that supports a role for tumor cell clusters in metastatic seeding—an alternative to the conventional view that metastases are seeded by single cells from the primary tumor.
Tumor cell clusters and polyclonal seeding of metastases
The idea that tumor cell clusters contribute to metastasis can be traced back to the 1950s, when it was reported that blood samples from cancer patients contain both single and clustered tumor cells and that tumor cell clusters can rapidly traverse the lungs in animal models. It was later shown that tumor cell clusters were more efficient than single cells were at producing metastases when injected intravenously into mice. However, because metastasis is known to be inefficient, the data from these early studies are consistent with two very different possibilities: Metastases could arise from a less efficient process of seeding by abundant single cells or from a more efficient process of seeding by rare clusters. Recent technological advances have revolutionized our ability to quantify circulating tumor cells (CTCs) and CTC clusters and to determine their molecular properties across diverse tumor types. In two such studies, the presence of CTC clusters was associated with significantly worse clinical outcomes as compared with the presence of single CTCs. Their prognostic value is consistent with the hypothesis that tumor cell clusters make a distinct contribution to metastasis.
If the metastatic seed is a single cancer cell, then the resulting tumor will be clonal. Conversely, if the seed is a CTC cluster, then the resulting metastasis can be polyclonal from the start. Deep-sequencing analysis of tumors allows the reconstruction of evolutionary histories of cancer cell clones during metastatic progression. These evolutionary histories can be used to infer monoclonal versus polyclonal seeding. One recent study of prostate cancer patients revealed evidence for frequent polyclonal seeding from the primary tumor to secondary sites and the polyclonal spread of existing metastases to new sites in the body. This observation emerges in the context of an expanding literature on phenotypic and genotypic diversity within primary tumors and an increased appreciation of cooperative and competitive dynamics among cancer cell clones. These studies suggest that different clonal combinations in the cluster could have very different properties with respect to growth and/or response to therapy.
Polyclonal metastases could arise in two distinct ways: direct seeding by a multicellular cluster or serial accumulation of multiple single cells at a common site. Mouse models have proved valuable in distinguishing between these two mechanisms. A key feature of these experiments is the ability to establish primary tumors containing a mixture of cancer cells that express fluorescent proteins of different colors. Both single cells and cell clusters composed entirely of the same color will generate singlecolored metastases (Fig. A). Conversely, clusters composed of more than one color will form multicolored metastases, which would provide direct evidence of their polyclonal origin (Fig. A and B).
Three independent research groups have conducted studies of this design using different mouse models, and all have found multicolored metastases, which is consistent with the concept that polyclonal metastases can be seeded by tumor cell clusters. The first group established multicolored mammary tumors in mice and frequently observed multicolored metastases. When they established a single-colored tumor on one side of the mouse and a different single-colored tumor on the other side, the metastases were predominantly single-colored. This result suggests that aggregation of tumor cells in the blood or at the distant organ is inefficient and, therefore, that multicolored metastases arise from seeding by tumor cell clusters. The second group extended the lineage analysis concept to pancreatic cancer, documented polyclonal seeding by clusters in the mice, and observed strong differences in the extent to which a polyclonal seed expanded into clonal or polyclonal metastases in different organ sites. Studying spontaneous breast cancer in mice, the third group quantitatively related the extent of clonal mixing in the primary tumor with the frequency of detection of multicolored metastases, leading them to estimate that >97% of metastases arose from clusters. These three studies also provided direct evidence that clusters exhibit superior survival and colony-forming potential both in culture and in vivo. Control experiments in which different color tumors were established in different locations in the mouse or different color cancer cells were injected intravenously at different times rarely or never yielded multicolored metastases. Therefore, all three studies provide data to support the concept that a multicellular cluster travels as a unit from the primary tumor to distant organs to seed polyclonal metastases.