Down’s Syndrome: Protection Against Cancer and the Therapeutic Potential of DSCR1

The past decade has seen a growing appreciation that cancers are not just clonal expansions of tumor cells but aberrant tissues, comprising many distinct cells types. As a tumor grows, it recruits a variety of accessory cells that underpin the angiogenesis and somatic remodeling necessary for tumor expansion. From this has evolved the notion that effective cancer therapies should combine agents that target not only the tumor cells themselves, but also the tumor microenvironment and, in particular, the generation and maintenance of the tumor blood supply – the process of tumor angiogenesis.

Tumor angiogenesis is a dynamic process involving continuous elaboration and remodeling of blood vessels in the tumor microenvironment. It is driven by the precocious production of various angiogenic factors, of which the best characterized is VEGF, an endothelial mitogen whose regulation and downstream effectors have been the focus of intense investigation for over a decade [1]. However, angiogenesis is under constant restraint by a variety of endogenous inhibitors, and it has become clear that modulation of these inhibitors also play a critical role in tumor angiogenesis, growth and progression, but the mechanisms by which they do so are far less well understood. While the regulation of VEGF and its receptors has been the focus of intense investigation for over a decade, the relative contribution to angiogenesis made by the various intracellular downstream effector pathways VEGF activates is not well defined [2]. In endothelial cells, however, a major consequence of VEGF receptor ligation is an abrupt increase in intracellular calcium triggering the activation of the serine/threonine phosphatase, calcineurin (or PP2B). We and others have demonstrated that calcineurin plays a pivotal role in VEGF signaling in endothelial cells: activated calcineurin dephosphorylates the nuclear factor of activated T cells (NFAT) family of transcription factors, triggering their nuclear entry and transactivation of pro-angiogenic genes, including cyclooxygenase-2 and E-selectin [3,4]. The Down’s syndrome candidate region-1 (DSCR1, RCAN1) gene is located on chromosome 21, and was originally identified by us and others as an endogenous regulator of the calcineurin-NFAT signaling pathway. More recently, we and others have shown that DSCR1 suppresses angiogenesis by blocking VEGF activation of endothelial cells via modulation of the calcineurin–NFAT pathway [5–9].

While a number of the epidemiological studies on Down’s syndrome and cancer come to slightly different conclusions regarding specific cancer types, the largest epidemiological study to date examined over 17,800 individuals with Down’s syndrome and found that mortality due to cancer (with the exception of leukemia and testicular cancer) occurs less than one-tenth as often as expected in comparison to age-matched non-Down’s syndrome individuals [10]. While there may be some bias in the interpretation of this and other studies, the protective anticancer effect of Down’s syndrome is quite significant. The significantly lower incidence of nearly all cancers in individuals with Down’s syndrome implies that one or more of the trisomic genes on chromosome 21 exerts a broadly antineoplastic effect, presumably by modulating some common, fundamental aspect of tumor initiation and/or progression.

Clinically detectable cancers are the rare outcome of an extended process that requires both tumor initiation and progression/growth. Whether it is incidence or progression that is the chief bottleneck in cancer evolution is a subject of some debate. However, there is a progressive accumulation of benign and/or indolent neoplasms that accumulate in many tissues through life: prominent examples include dysplastic nevi in the skin, prostatic intraepithelial neoplasias, thyroid carcinoma in situ, dysplastic ductal foci in breast and pancreatic intraepithelial neoplasia. The relatively large numbers of such lesions compared with the much lower incidence of clinically detectable tumors indicates that many initiated tumors stall at some earlier phase of tumor development [11]. Thus, tumor initiation events greatly outnumber frank cancers. Our recent work suggests that progression and expansion of tumors, not initiation, is the critical component of tumorigenesis that may be suppressed in Down’s syndrome [12]. We propose that the progression of dormant microscopic lesions into macroscopic, invasive and metastatic tumors occurs at a significantly reduced frequency in individuals with Down’s syndrome and that this process is mitigated, in part, by the attenuation of the VEGF–calcineurin signaling axis due to the extra copy of DSCR1along with other genes on chromosome 21. We have shown that the modest excess of DSCR1 arising from trisomy plays a key role in maintaining a nonpermissive antiangiogenic tumor environment, thereby blocking the progression of initiated tumors. While our recent work focused on the contribution of DSCR1 towards angiogenic suppression in Down’s syndrome, our data clearly indicate that while DSCR1 trisomy plays a significant role, it is not the only gene on chromosome 21 involved in suppressing tumor angiogenesis [12]. Other candidate antiangiogenic genes located on chromosome 21 include: collagenXVIII, the precursor to the endogenous angiogenesis inhibitor endostatin [13,14]; ADAMTS1, the matrix metalloproteinase that regulates the antiangiogenic function of thrombospondin-1 [15,16]; and DYRK1A, a kinase known to negatively regulate the calcineurin pathway together with DSCR1, but whose function has not yet been fully explored in endothelial cells [17,18].

Given that individuals with Down’s syndrome harbor a third copy of chromosome 21 from conception, it is of interest to note that physiologic angiogenesis appears to be relatively unaffected in these individuals. Recent studies have indicated that the genes and signaling pathways regulating physiologic angiogenesis are distinct and separable from pathologic angiogenesis [19]. This suggests that the genes contributing to angiogenic suppression located on chromosome 21 may play a more significant role in regulating pathologic rather than physiologic angiogenesis. Another intriguing clinical clue provided by this unique population suggests that antiangiogenic therapy may be most effective if delivered as a preventative, low-dose and long-term regimen. We postulate that expression of chromosome 21 genes beginning during embryogenesis in Down’s syndrome individuals allows the modest overexpression of these genes to effectively prevent microscopic dormant tumors from undergoing an angiogenic switch due to their sustained long-term expression. It is possible that antiangiogenic therapy may be most effective if utilized as prophylactic treatment of individuals at high risk of developing cancer, such as women with mutations in the Breast cancer susceptibility gene (BRCA1) or patients who have had primary tumors resected and are at high risk for recurrence.

Determining the specific role that DSCR1 plays in cancer protection in individuals with Down’s syndrome may potentially identify DSCR1 as a therapeutic target for tumor prevention and therapy. Since DSCR1 is an inhibitor of calcineurin, to determine whether DSCR1 can be translated into a therapy it will be important to understand its mechanism of calcineurin inhibition. While calcineurin inhibitors such as the immunosuppressant cyclosporin A and FK506 are readily available, long-term cyclosporin A treatment is known to lead to an increased incidence of cancer. As compared with an age-matched healthy population or with patients undergoing dialysis, cyclosporin A-treated patients have a significantly increased incidence of cancer [20]. Indeed studies have found that patients on long-term cyclosporin A therapy have a 20–40% increased risk of developing cancer as compared with untreated age-matched individuals [21]. The mechanism behind this increase in tumor growth mediated by cyclosporin A is unclear, but may be due in part to upregulation of TGF-β, a molecule known to promote tumor cell invasion and metastases [22]. Unpublished studies from our laboratory indicate that calcineurin inhibition by DSCR1 is mechanistically distinct from that of cyclosporin A, leading us to hypothesize that this difference may underlie their contrasting effects on tumorigenesis. The mechanism of calcineurin inhibition by cyclosporin A, as well as the crystal structure of cyclosporin A bound to calcineurin, has been previously described [23]. Cyclosporin A complexed to its intracellular docking protein cyclophilin B does not bind directly to the active site but functions by preventing substrate access to the catalytic site of calcineurin [24]. Understanding the mechanism by which DSCR1 exerts its inhibitory effect on calcineurin will be important for the development of novel calcineurin inhibitors that block calcineurin-dependent angiogenesis without increasing cancer risk.

Our recent study examining the contribution of chromosome 21 genes to cancer protection in the Down’s syndrome population has broad implications for tumorigenesis, in general, and the role of calcineurin signaling in tumor angiogenesis in particular [12]. While more studies are necessary, it is reasonable to speculate that regulation of the calcineurin pathway may be a critical determinant of neoplastic risk in all individuals. Targeting tumor angiogenesis has emerged as an important and distinct therapeutic modality in cancer therapy, focused on preventing endothelial activation by sequestering angiogenic factors or blocking their receptors. With the presence of at least four genes on chromosome 21 that function to negatively regulate angiogenesis by different mechanisms, it will be of great interest to determine whether long-term, low-dose combination therapy with DSCR1, DYRK1A, endostatin and ADAMTS1 may offer broad cancer protection in all individuals and define a new modality of antiangiogenic therapy.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.