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    Tumor Blood Vessels Orchestrate The Birth Of Cancer Stem Cells
    By Jennifer Wong | February 4th 2013 05:43 PM | 1 comment | Print | E-mail | Track Comments
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    My column covers the latest primary research discoveries in the life-science discipline. Much of what is reported here are considered discoveries...

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    Like blood vessels that supply oxygen and nutrients to normal tissue, tumor blood vessels were originally thought to do likewise to fuel tumor growth. As scientists developed strategies to kill tumors by cutting off their blood supply, they soon discovered their valiant efforts were thwarted by the tumor's ability to quickly recover.

    The recovery is caused by a population of tumor-initiating cancer cells dubbed the cancer stem cells (CSCs); a population that can communicate with blood vessels via the Notch signaling pathway to drive tumor vascularization.

    It turns out that this "Notch" communication can go both ways. In a Cancer Cell study, scientists discovered that tumor-blood vessels can communicate with cancer cells via Notch signaling, and direct their transformation into cancer stem cells. Specifically, the authors found that when colorectal cancer cells are exposed to tumor endothelial cell directly or indirectly via conditioned medium, these cells acquire features that resemble CSCs.

    Some of these features include their expression of the stem cell marker CD133, their ability to initiate colorectal cancer when transplanted elsewhere, and their marked resistance to chemotherapy.

    The authors further found that the Notch signaling is driven by the release of soluble Jagged-1 from the surface of endothelial cells, a process driven by a membrane enzyme ADAM17. Jagged-1 binds to Notch-1 and triggers downstream activation of the transcription factors Hes1 and NICD in cancer cells to drive their transformation into CSCs.  

    Supporting this preclinical data, the authors found that colorectal CSCs are closely associated tumor blood vessels in clinical surgical specimens of colorectal cancer. Using a Notch signaling reporter system to track Hes1 and NICD in surgical specimens, the authors were able to confirm that Notch signaling is indeed active in colorectal cancer cells/stem cells surrounding tumor blood vessels.

    This study first evidence suggesting that tumor-blood vessels are not merely conduits of nutrients and oxygen, but are also a communication hub that orchestrates the birth of cancer stem cells- the drivers of tumor initiation.

    Reference:

    Lu et al., Endothelial Cells Promote the Colorectal Cancer Stem Cell Phenotype through a Soluble Form of Jagged-1, Cancer Cell (2013), http://dx.doi.org/10.1016/j.ccr.2012.12.021

    Comments

    gpawelski

    Pathways known to be important for normal stem cell self-renewal, such as the Wnt, Notch and Hedgehog pathways are now of increased interest due to their potential role in cancer stem cells (CSCs).

    Resistance to VEGF inhibitors has emerged as a major clinical problem. Notch signaling has been implicated in tumor angiogenesis. Notch signaling may enhance the efficacy of VEGF inhibitors.

    While many labs have investigated Notch inhibitors and others have investigated CSCs, some labs have a unique approach that combines both in a three-dimensional (3D) culture that mimics what happens in patients.

    Cell-based functional profiling labs have recognized the interplay between cells, stroma, vascular elements, cytokines, macrophages, lymphocytes and other environmental factors. This lead to their focus on the human tumor primary culture microspheroid (microclusters), which contains all of these elements.

    In their earlier work, they endeavored to isolate tumor cells from their benign constituents so as to study “pure” tumor cells. As time went on, however, they found that these disaggregated cells were artificially sensitized to the effects of chemotherapy and provided false positive results in vitro.

    Early work by Beverly Teicher and Robert Kerbel that examined cells alone and in three-dimensional (3D) structures, lead to the realization that cancer cells inhabit a microenvironment. Functional cytometric profiling labs now study cancer response to drugs within this microenvironment, enabling them to provide clinically relevant predictions to cancer patients.

    It is their capacity to study human tumor microenvironments that distinguishes them from other lab platforms in the field. And, it is this capacity that enables them to conduct discovery work on the most sophisticated classes of compounds that influence cell signaling at the level of notch, hedgehog and WNT, among others (Gonsalves, F, et al. (2011).

    An RNAi-based chemical genetic screen identifies three small-molecule inhibitors of WNT/wingless signaling pathway (PNAS vol. 108, no. 15, pp. 5954-5963). With this clinically validated platform they are now positioned to streamline drug development and advance experimental therapeutics.