When metastasis ‘Spns’ out of control: Coverage of ‘Genome‐wide in vivo screen identifies novel host regulators of metastatic colonization’
Year: 2017
Type: article
Abstract: Metastasis is the major cause of death from cancer in patients. Invasive tumor cells that leave the primary tumor must undergo a strenuous journey including extravasation, survival in the blood, intravasation into the distal site, and proliferation in a new microenvironment to form metastatic colonies. The tumor cells that are successful in forming colonies have dodged multiple perils including evading immune defenses and oxidative stress in the circulatory system. A small number of cells which leave the tumor and circulate through the blood reach the lung, and an even smaller number of tumor cells survive in the lung microenvironment, and proliferate to form metastatic foci (Fukuhara et al., 2012). Disseminated tumor cells may become dormant and take several years to ultimately grow out and form overt metastases (Massague & Obenauf, 2016). This dormancy is maintained in three ways: by cellular dormancy, where the cells themselves remain in a slow-cycling state; by angiogenic dormancy, where micrometastatic populations do not have the nutrient supply to overcome their dormant state; and finally, by immune-mediated dormancy, where the immune system kills some tumor cells, keeping the micrometastatic populations in check. The role of immune-mediated tumor dormancy has been highlighted by clinical evidence in patients receiving kidney transplants from donors who had previously had melanoma, but who were declared to be tumor-free. Recipients of donor organs went on to develop melanoma in the transplanted kidneys (Mendoza et al., 2012). It is thought that the immunosuppressant drugs taken by these organ recipients allowed for the rapid outgrowth of the melanoma metastases, thus highlighting the importance of the immune system in maintaining tumor dormancy. Using an elegant in vivo screen, where 810 mutant mouse cell lines were screened, van der Weyden et al. have further confirmed the critical role of the host immune microenvironment in the establishment of metastases. Van der Weyden et al. identified 23 genes, which regulate metastatic colonization of the lung. Of these genes, 19 are genes previously unknown to modulate host control of metastatic colonization. While genes associated with multiple cellular processes were identified, the majority had important roles in the immune regulation of metastatic outgrowth. In this study, pulmonary metastatic colonization was found to be suppressed by eight genes (Irf1, Rnf10, Pik3cg, Dph6, Slc9a3r2, Irf7, Abhd17a), two of which are members of the interferon regulatory family (Irf1 and Irf7), which is important for immune function. While interferons have previously been implicated in the regulation of metastasis, very little is known about the microenvironmental function of the Rnf10, Dph6, Slc9a3r2, and Abhd17a genes in suppressing metastasis. Another 11 genes previously unknown to regulate metastatic colonization were also identified (Grsf1, BC017643, Fam175b, Bach2, Ncf2, Arhgef1, Fbxo7, Tbc1d22a, Lrig1, Cyba, Spns2). Of these genes, the authors chose Spns2 to explore in greater depth, as the manipulation of Spns2 had a profound impact on metastatic burden. Spns2, the sphingosine-1-phosphate transporter spinster homologue2, is a cell surface transporter on endothelial cells which allows for the secretion of sphingosine-1-phosphate (S1P) into the blood and lymph (Nagahashi et al., 2013). Previous studies suggest that Spns2 is largely responsible for lymphatic concentrations of S1P, but plays less of a role in blood concentrations of S1P (Senft & Ronai, 2016). Secretion of S1P into blood and lymph creates an S1P gradient, which promotes the egress of newly formed T cells from the thymus and B cells from the bone marrow (Strauss & Thomas, 2010). S1P is a sphingolipid which signals through extracellular G-coupled protein receptors (S1PR1-5), such as S1PR1 on T cells and B cells and S1PR5 on natural killer (NK) cells. S1P is important in vascular signaling, playing a role in angiogenesis and vascular permeability, as well as immune cell trafficking. Van der Weyden et al. found S1P to be increased in the lungs and decreased in the blood of Spns2tm1a/tm1a mice; however, there was no difference in vascular permeability. ‘...Spns2 [is revealed]... to be an attractive therapeutic target for decreasing metastatic burden in a variety of cancer types’ Global alteration of Spns2 in host mice was found to decrease the number and size of foci in the lungs following intravenous (I.V.) administration of lung, colon, and breast cancer cells; however, alteration of Spns2 did not affect the growth of primary tumors. The decrease in metastatic foci was not due to a reduction in the number of cells arriving to metastatic sites, but rather an increase in apoptosis shortly after their arrival. The apoptosis appears to be immune mediated as specific deletion of Spns2 in lymphatic endothelial cells recapitulated the phenotype. Interestingly, global or lymphatic endothelial-specific deletion of Spns2 causes a circulating lymphopenia, and overall decrease of T cells and B cells in the lung following I.V. injection of tumor cells. However, there is an increase in NK cells, the ratio of effector memory T cells to regulatory T cells, and the percentage of CD8+ cells expressing CD107a and intracellular IFN-gamma in the lung, all indicators of an increased immune response (Figure 1). This increased response in the lung correlates with tumor cell death and an overall decrease in metastatic burden, suggesting that the microenvironment in Spns2tm1a/tm1a mice is hostile to the tumor cells. In contrast, while altering Spns2 increases NK cells in the lungs, there is no difference in the number of NK cells in the circulatory system, compared to a global loss of both T and B cells. To identify which immune populations were important in decreasing metastatic foci in Spns2tm1a/tm1a mice, the authors individually depleted CD8+ T cells and NK cells. In both cases, depletion of the target cell population did not fully eliminate Spns2-mediated decreases in pulmonary metastases. However, co-depletion of both CD8+ and NK cells resulted in the full restoration of metastatic burden in Spns2 mutant mice. These data suggest that both CD8+ T cells and NK cells contribute to the decrease in metastatic foci observed in Spns2tm1a/tm1a mice. It is also possible that either altered endothelial cell function or lung S1P levels also contribute to decreased metastatic foci observed in these mice. This study is unique in its genome-wide approach to the identification of critical host regulators of tumor cell colonization of metastatic sites. Investigating the role of Spns2 in regulating colonization reveals it to be an attractive therapeutic target for decreasing metastatic burden in a variety of cancer types, as it exerts effects on the microenvironment rather than the tumor cell. However, inquiry into the toxicity of targeting Spns2 still needs to be explored. In addition, Spns2 plays critical roles in the seeding of metastatic populations, due to immune-mediated killing which alters the overall population of disseminated cells. This has important implications not just for metastasis but for tumor dormancy as well.
Source: Pigment Cell & Melanoma Research
DOI: 10.1111/pcmr.12588
Language: English
Topic: Cancer Cells and Metastasis
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funder: National Cancer Institute
OpenAlex ID: W2597272080