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The American Journal of Pathology, Vol. 184, No. 5, May 2014
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MINI-REVIEW CD133-Targeted Niche-Dependent Therapy in Cancer A Multipronged Approach Anthony B. Mak,*y Caroline Schnegg,* Chiou-Yan Lai,z Subrata Ghosh,* Moon Hee Yang,* Jason Moffat,y and Mei-Yu Hsu*z From the Department of Dermatology,* Boston University Medical Center, Boston, Massachusetts; the Banting and Best Department of Medical Research,y University of Toronto, Toronto, Ontario, Canada; and the Department of Pathology,z Brigham and Women’s Hospital, Boston, Massachusetts CME Accreditation Statement: This activity (“ASIP 2014 AJP CME Program in Pathogenesis”) has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Society for Clinical Pathology (ASCP) and the American Society for Investigative Pathology (ASIP). ASCP is accredited by the ACCME to provide continuing medical education for physicians. The ASCP designates this journal-based CME activity (“ASIP 2014 AJP CME Program in Pathogenesis”) for a maximum of 48 AMA PRA Category 1 Credit(s). Physicians should only claim credit commensurate with the extent of their participation in the activity. CME Disclosures: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose.
Accepted for publication January 16, 2014. Address correspondence to Mei-Yu Hsu, M.D., Ph.D., Department of Dermatology, Boston University Medical Center, 609 Albany St, J-410, Boston, MA 02118. E-mail:
[email protected].
Cancer treatment continues to be challenged by the development of therapeutic resistances and relapses in the clinical setting, which are largely attributed to tumor heterogeneity, particularly the existence of cancer stem cells (CSCs). Thus, targeting the CSC subpopulation may represent an effective therapeutic strategy. However, despite advances in identifying and characterizing CD133þ CSCs in various human cancers, efforts to translate these experimental findings to clinical modalities have been slow in the making, especially in light of the growing awareness of CSC plasticity and the foreseeable pitfall of therapeutically targeting CSC base sorely on a surface marker. We, and others, have demonstrated that the CD133þ CSCs reside in complex vascular niches, where reciprocal signaling between the CD133þ CSCs and their microenvironment may govern niche morphogenesis and homeostasis. Herein, we discuss the multifaceted functional role of the CD133þ cells in the context of their niche, and the potential of targeting CD133 as a niche-dependent approach in effective therapy. (Am J Pathol 2014, 184: 1256e1262; http://dx.doi.org/10.1016/j.ajpath.2014.01.008)
Solid tumors and hematopoietic cancers are morphologically and functionally heterogeneous, which is believed to be attributed to subpopulations of tumor cells with stem cellelike properties, termed cancer stem cells (CSCs). Such as their normal stem cell counterparts, CSCs are primitive cell entities able to self-renew and asymmetrically divide to maintain a stem cell pool, as well as differentiated cell progenies.1 On the basis of these criteria, CSCs have been isolated or enriched from numerous tissue types and demonstrated to exhibit increased resistance to conventional cancer treatments, including chemotherapy and radiotherapy, which can be partially explained by their quiescence, up-regulation of efflux transporters, and increased ability for DNA damage repair.1 Taken together, CSCs may explain cancer relapses and metastases, which have led to Copyright ª 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajpath.2014.01.008
the argument that targeting CSCs may yield improved survival and treatment outcomes for patients. The identification and characterization of CSCs is largely owed to the use of cell-surface markers. Although this approach has been widely applied for a range of solid tumors and hematopoietic cancers from varying tissue types, there is evidence that the CSC phenotype may be acquired or induced in cancer cells lacking CSC markers, such as glioma or Supported in part by National Cancer Institute, NIH, grant R01 CA138649 (M.-Y.H.); the Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School (Boston, MA) start-up fund (M.-Y.H.); and a Mach-Gaensslen Foundation of Canada grant (A.B.M.). J.M. holds a Tier 2 Canada Research Chair in Functional Genomics of Cancer. Disclosures: None declared.
Targeting CD133 in Cancer Treatment pancreatic cancer cells.2,3 These observations challenge the hierarchical CSC hypothesis and propose a stochastic model, whereby non-CSCs can acquire stem cell properties through mutations or external cues.2 Thus, stem cell properties of tumor cells are dynamic, and strategies that solely target CSCs may not be effective because CSCs may be replenished through phenotypic switching from non-CSCs. CD133 is an approximately 120-kDa pentaspan transmembrane glycoprotein that is primarily localized to the plasma membrane, and its cell-surface epitope, AC133, has been highly used as a cell-surface marker to isolate and enrich for CSCs from a wide range of tissue types.4 Consistent with its role as a CSC marker, CD133 expression has been associated with increased chemoresistance and radioresistance, as well as a poor prognosis in various cancers.4,5 However, its utility as a CSC marker has been the subject of controversy because CD133 has been demonstrated to be expressed in differentiated cell populations,4 and the CD133e fractions have been shown to initiate tumor in vivo.6,7 We, and others, have partially addressed this concern by demonstrating that the AC133 epitope is regulated by specific CD133 N-glycosylation processing,8,9 as well as alternative splicing.10 Indeed, cellsurface AC133 appears to be specific to stem cell populations and is lost during differentiation, whereas CD133 protein and mRNA expression can be maintained.8 Furthermore, the tumorigenic property of CD133 tumor subsets is believed to arise in cancer cells that either harbor masked CD133 epitopes11 or subsequently induced CD133 because of environmental cues.2,3 Compelling evidence suggests that certain CD133 glycoforms not only serve as a marker for CSCs, but also contribute to cell survival, maintenance of stemness, and tumorigenesis.12e14 In addition, recent findings have linked CD133 to tumor vascularization, because it appears to be required not only for angiogenesis, such as in brain tumors,15 but also vasculogenic mimicry (VM) in melanoma,12 beast,16 and brain17 cancers. Despite these advances, the functions of CD133 in various cancer types at the cellular and molecular levels remain an underdeveloped area of research. In this review, we will discuss the known and hypothesized roles of CD133-expressing subsets in the vascular niche and their potential as targets for niche-dependent therapy.
brain tumor stem/initiating cells, resulting in growth arrest.18 Correspondingly, similar vascular niches of CD133þ CSCs have also recently been identified in melanoma, albeit in a more complex context of tumor microcirculation.12 The VM, originally described in uveal melanoma,19 connotes the PAS-positive, patterned networks and channels lined externally by CD31 tumor cells with endothelial phenotypes, such as CD144 (vascular endothelial cadherin), Tie-1, and EphA2 expression.20e22 The documentation of intraluminal blood cells within the VM channels and mosaic vessels partially lined by VM-engaging tumor cells and bona fide CD31þ endothelial cells and the reported up-regulation of genes involved in anti-coagulation mechanisms in VMengaging tumor cells have provided evidence for the perfusability of VM networks.22 Therefore, VM networks constitute an alternative mechanism for nutrient supply and act as a potential access point for metastases.5 To date, VM has been observed in a broad range of cancer types, including, but not limited to, melanoma, glioblastoma, astrocytoma, various carcinomas, and sarcoma,23e27 and is associated with increased tumor aggressiveness23 and patient mortality.28 Expression gene profiling using microarray analyses reveals that VMengaging melanoma cells exhibit a pluripotent, primitive phenotype, co-expressing multiple lineage-specific genes, including those of endothelial, epithelial, fibroblastic, hematopoietic, renal, neuronal, muscular, and precursor/progenitor cell types.29 These findings suggest that the VM-engaging
Vascular Niche of CD133D CSCs Significance of VM Like normal stem cells, CSCs exist in specialized compartments within the tumor known as niches. Such niches provide the essential cues for cell fate determination, by achieving a balance between self-renewal and differentiation. For example, Calabrese et al18 demonstrated that the CD133þ brain cancer stem cells are localized to the perivascular microenvironment, the so-called perivascular niche. Disruption of such perivascular niches ablates the CD133þ
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Figure 1 The complex vascular niche of CD133þ CSCs in melanoma. CD133þ CSCs reside in a complex anastomosing microvascular niche encompassing CSC-lined VM channels, mosaic vessels, and authentic blood vessels lined by bona fide ECs. CSCs may contribute to niche morphogenesis through vascular endothelial growth factor (VEGF) secretion, which then induces multiple pathways for niche vascularization, including vasculogenic mimicry (1), direct transdifferentiation of CD133þ CSCs to CD31þ tumor-derived endothelium (2), and recruitment of ECs (3) and EPCs (4) for angiogenesis.
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Mak et al melanoma cells possess stem cellelike properties with phenotypic plasticity to serve endothelial function. We previously reported that the CD133þ melanoma CSC subsets coincide with the areas of VM in a complex anastomosing microvascular niche, encompassing CD144þ melanoma-lined VM channels, mosaic vessels, and authentic endothelial cellelined blood vessels (Figure 1).12 Double immunofluorescence reveals that the spatial arrangement of putative marker-positive melanoma CSC subsets within the vascular niche is not random. In most cases, there appears to be complete overlap between the perivascular CD133þ and CD144þ subsets (Figure 2A). At times, the CD133þ subset partially overlaps with the CD144þ fraction, with the latter exhibiting a more restricted perivascular pattern (Figure 2, B and C). On the rare occasion, a mutually exclusive zonal pattern, in which the CD144þ VM-engaging subset closely approximates the CD31þ endothelium-lined blood vessels with abrupt transition to the CD133þ subpopulation radially, is observed (Figure 2D).
These findings suggest a zonal gradient of microenvironmental cues within the vascular niche in controlling the CSC phenotype. Deciphering the molecular signals in the vascular niche that governs CSC phenotype presents a golden opportunity for novel therapeutic targets taking advantage of the codependence between CSCs and their niches.
Colocalization of CD133þ CSCs and CD144þ vasculogenic mimicry-engaging tumor subsets to vascular niche in melanoma xenografts. Double-immunofluorescence staining in consecutive sections (left and right panels) demonstrates different spatial arrangements of the CD133þ and CD144þ CSC subsets within vascular niches of WM1617 melanoma xenografts [anti-CD31 (red) decorates endothelium (EC)-lined blood vessels]: A: Complete overlap of perivascular CD133þ (left panel, green) and CD144þ (right panel, green) subpopulations. B and C: Partial overlap of the CD144þ population (right panel, green) with a subset of CD133þ cells (left panel, green) perivascularly. D: Mutually exclusive zonal arrangement with the CD144þ population (right panel, green) intimately associated with CD31þ endothelium-lined blood vessels, which abruptly transits to the CD133þ population peripherally (left panel, green).
Perivascular Niche and Maintenance of the CSC Phenotype
Figure 2
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CD133þ CSC Subsets Contribute to VM Interestingly, CD133þ CSCs have been shown to induce VM channels in triple-negative breast cancer16 and glioblastoma,17 characterized by their enrichment of CD144 and downstream up-regulation of the matrix metalloproteinases 2 (MMP-2) and 9 (MMP-9), which cleave the extracellular matrix (ECM), laminin 5 subunit g2 (LAMC2).5 Consistently, we found that down-regulating CD133 with RNA interference resulted in decreased VM formation in melanoma xenografts.12 Although the molecular mechanism underlying VM modulation by CD133 is presently unknown, we have recently demonstrated that CD133 upregulates LAMC2 transcriptional expression via b-catenin signaling in colorectal and ovarian carcinoma cell lines,30 suggesting that CD133 contributes to VM induction by regulating the ECM (Figure 3). The observations that LAMC2, MMP-2, and MMP-9 colocalize to VM channels and that ECM deposited by VM-forming tumor cells induces VM in nonaggressive melanoma cells, and even normal melanocytes,31 further support the hypothesis that VM-engaging CSCs may modulate the local ECM composition to promote VM32 and, thereby, perivascular niche morphogenesis. Indeed, targeting the ECM component, LAMC2, in melanoma resulted in inhibition of VM initiation.32,33 In addition, CD133þ glioblastoma stem cells that underwent VM formations display increased expression of vascular endothelial growth factor (VEGF) and other proangiogenic factors,34 and VEGF knockdown in osteosarcoma abolishes VM.35 VEGF may regulate VM formation via an autocrine signaling, because Adini et al15 recently showed that CD133 interacts with VEGF and potentiates its action in both melanoma and vascular endothelial cells (Figure 3). Taken together, CD133þ fractions contribute to VM through multiple mechanisms, including modulating pro-VM ECM and up-regulating and potentiating VEGF (Figure 3).
In addition to inducing VM, ample evidence suggests that VM/niche-associated ECM may also regulate stemness. For example, galectin-3, a member of the lectin family, positively regulates CD144 expression and its downstream effector molecule, MMP-2, in melanoma (Figure 3).36 Consistently, silencing galectin-3 expression prevented VM formation and invasion of an aggressive cutaneous melanoma cell line in vitro and in vivo.36 Moreover,
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Targeting CD133 in Cancer Treatment secrete certain factors in the perivascular niche to promote brain CSC self-renewal and tumorigenesis.18 However, whether VM channels secrete factors or provide direct cell contact to maintain and protect CD133þ CSCs is presently unknown. Given that we demonstrated that CD133þ melanoma stem cells reside adjacent to authentic endothelial-lined vessels, mosaic vessels, and VM channels (Figure 1), we hypothesize that multiple vascular forms contribute to the perivascular niche in melanoma, and that a continuum, or gradient, of vessel forms collaborates to establish the perivascular niche. Comparing the contributions of varying vascular forms to the perivascular niche will be an ongoing effort.
CD133 Subsets Contribute to Angiogenesis of Endothelium-Lined Blood Vessels via Dual Mechanisms Reciprocal signaling between CD133þ CSCs and their vascular niches contributes to niche morphogenesis and CSC maintenance. Data suggest that both the CSCs and the niche contribute to the niche morphogenesis and homeostasis. For example, the CD133þ CSCs may activate VM via VEGF- or b-cateninedependent mechanisms, leading to deposition of LAMC2 in the niche microenvironment, which, in turn, enhances VM through a feedback loop. In addition, CD133þ CSC-derived VEGF aids in tumor angiogenesis through endothelial cell (EC)-, EPC-, and CSCmediated mechanisms. Conversely, niche-associated extracellular matrix galectin-3 can induce CD133 expression, and the VM phenotype (through induction of CD144 and MMP2), in cancer cells. Depletion of galectin-3 results in the loss of the CD133þ subset and abolishes VM.
Figure 3
galectin-3 is involved in promoting cell-surface expression of the CD133 epitope, AC133, a marker specific to stem cellelike states, in human embryonic kidney 293 cells (Figure 3).9 These findings suggest that reciprocal interactions between tumor cells and VM/niche-associated ECM, such as galectin-3, may regulate CSC phenotype and perivascular niche morphogenesis. It is not entirely clear why CSCs reside in the perivascular niche. In our perspective, this particular location allows CSCs access to endothelial cells and endothelial stem and progenitor cells (EPCs) to efficiently and conveniently orchestrate complex microcirculatory networks to secure nutrient supply; these networks are composed of authentic blood vessels, through angiogenesis, and tumor-derived circulatory networks, via transdifferentiation into CD31þ tumor-derived endothelium (described in CD133 Subsets Contribute to Angiogenesis of Endothelium-Lined Blood Vessels via Dual Mechanisms) or CD31, CD144þ VM channels. The proximity of the CSC niche to tumor vasculature would also facilitate delivery of endocrine and environmental cues involved in initiating and maintaining CSCs, a hypothesis that would be consistent with the stochastic model. In response to these external cues, CSCs undergoing invasion to adjacent tissues or metastasis would have a less structurally obstructed route, being in contact with the systemic circulation. Along with the blood-borne endocrine and environmental cues, endothelial cells residing in brain tumors
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Tumor vasculature provides an exchange of nutrients and waste to support tumor growth and progression, as well as laying a route for metastasesda significant cause of cancerrelated morbidity and mortality. Various mechanisms participate in tumor vascularization, including nonsprouting and glomeruloid angiogenesis, postnatal vasculogenesis, intussusceptive microvascular growth, and the previously mentioned VM.5,37 The varying forms of tumor vasculature may be explained by plastic CSC and EPC populations that can differentiate into endothelium or endothelium-like structures. In fact, the CD133 fraction in ovarian tumors is composed of the CSC subset and EPCs that are capable of differentiating into vascular networks.38 For example, in response to environmental stresses, such as nutrient starvation and hypoxia, hepatocellular carcinoma cells can secrete pro-angiogenic factors, which actively recruit CD133þ and VEGF receptor-2 (VEGFR-2)þ EPCs from local pre-existing capillaries or from the bone marrow to initiate tumor neovascularization.39,40 CD133þ EPCs are not always recruited from local preexisting capillaries or the bone marrow, but can also be derived from neoplastic origins (Figure 1). Although considered an endothelial protein in normal tissues, VEGFR-2 is also preferentially expressed on CD133þ glioma stem-like cells (Figure 3).41 Therefore, in addition to its paracrine role in recruiting host EPCs, it is thought that tumor-secreted VEGF can serve as an autocrine signal via tumor-expressed VEGFR-2 (Figure 3). This is supported with the report that VEGF is up-regulated in CD133þ medulloblastoma cells compared with their CD133 counterparts.42 The importance of the VEGF/VEGFR-2/neuropilin 1 prosurvival signaling has been shown in endothelial cells, which are required in tumor initiation and growth, as well as maintaining CSC self-renewal in skin tumors.43 Moreover, CD133þ brain tumor stem cells can differentiate into tumor EPCs that then participate in angiogenesis by further differentiating into progeny resembling an endothelial phenotype and expressing endothelial markers, including CD31 (Figure 1).44e47
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Mak et al Recently, VEGF has been shown to be a direct physical interaction partner of CD133. Specifically, soluble CD133 promotes the formation of VEGF165 dimers that are required for binding to its VEGF receptors (Figure 3).15 These findings support the notion that CD133 contributes to tumor vascularization via a VEGF signaling mechanism (Figure 1).15 Indeed, it has been demonstrated that targeting CD133 in both primary human endothelial cells and in a melanoma cell line results in aberrant and reduced tumor microcirculation.15 Taken together, tumor angiogenesis may be regulated through the interplay between VEGF, VEGF receptors, and CD133-expressing EPCs, as well as tumor cellederived EPCs.
Targeting CSCs and the Vascular Niche via CD133 In both the CSC hierarchical and stochastic models, targeting existing CSCs and the induced new CSCs has been proposed to be an effective strategy for cancer treatment. Targeting CSCs can be achieved by direct approaches, or possibly by impinging on the structure and function of their vascular niche. The latter would particularly serve the stochastic model because niche-dependent targeting strategies may prevent the induction of dedifferentiation of cancer cells into CSCs. Because recent studies have demonstrated that CD133 is required for CSC identity, and for angiogenesis15 and VM,12 which ultimately establishes the vascular niche, we propose that targeting CD133 expression or activity may disrupt the reciprocal signaling between the CD133þ CSCs and their vascular niche, responsible for the maintenance/induction of the CSC phenotype. Furthermore, given the discussion of various tumor vascularization mechanisms previously described, CD133 appears to serve a role in deriving both normal and neoplastic endothelium, as well as VM, suggesting that it contributes to vascular niche morphogenesis regardless of the vessel type involved (Figure 3). Thus, CD133 targeting bypasses the pitfall of tumor plasticity by not only undertaking the pre-existing CSCs but also preventing niche-dependent induction of CSCs from the non-CSC populations through inhibition of angiogenesis and VM. Another niche-dependent approach includes targeting EPC recruitment to tumor sites using anti-angiogenesis therapies. Although traditionally the objective of this approach would be to block the supply of oxygen and nutrients required for tumor survival and the route for metastases, it would also serve to abolish the vascular niche and disrupt residing CSCs. This would be a particularly attractive approach as the vascular niche maintains CSCs in a quiescent and prosurvival state, which ultimately shields them from anticancer therapies. Although targeting tumor angiogenesis using the anti-VEGF monoclonal antibody therapy has provided some promising preliminary findings in xenograft mouse models harboring brain tumors,18 it has
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had minimal benefits in patient survival rates.48,49 This could be explained by the existence of tumors that have either adapted or adopted VEGF-independent vascularization mechanisms, VEGF resistance, and other redundant pathways. We have focused herein on the hypothesis that VEGF signaling may be involved in VM and transdifferentiation of tumor cells into endothelium-like cells; however, it is certainly possible that these vasculogenic pathways may exist independently from VEGF. Furthermore, anti-angiogenesis treatments may encourage tumor adoption of alternative vascularization mechanisms, such as VM, that are resistant to anti-angiogenesis therapies, resulting in increased tumor invasiveness and metastases.50 This makes it particularly important to consider combination therapies that address both tumor cell (CSCs in particular) and endothelium-derived vascularization mechanisms. In support of targeting CD133, we have recently shown that targeting the histone deacetylase 6 (HDAC6) expression or its activity reduces CD133 stability and signaling, resulting in reduced tumorigenesis, as well as increased cancer cell death and differentiation in colon and ovarian adenocarcinoma.30 More important, no physiological differences were reported in an HDAC6 knockout mouse model compared with wild-type mice,51 suggesting that HDAC6 may be dispensable in normal cells, but not cancerous ones. One concern of using drugs or molecules that target CD133 in cancer stem and progenitor cells is the result of retinal degeneration and vision loss as mouse models and patients carrying certain CD133 gene mutations acquire progressive retinal degeneration and blindness.4 However, it is possible that small-molecule inhibitors targeting CD133 may be blocked from CD133þ retinal progenitor cells because of the blood-ocular barrier, thus preventing retinal degeneration and loss of vision. On the basis of the current data, we propose that targeting CD133 would be a novel and viable approach for cancer treatment, in part by inhibiting various tumor vascularization mechanisms and abolishing the CSCs simultaneously. Although we, and others, have demonstrated that silencing CD133 using RNA interference results in a significant reduction in tumor vascularization and size, further experiments using anti-CD133 blocking antibodies or HDAC6 small-molecule inhibitors in xenograft mouse models are warranted. These in vivo studies in mouse models are particularly important to investigate the impact of targeting CD133 in CD133þ normal stem and progenitor cell populations, such as those in the retina, for potential adverse effects.
Conclusions and Future Challenges CD133þ CSCs are not randomly distributed but reside in a complex vascular niche, encompassing authentic endothelium-lined blood vessels, tumor-derived VM channels, and mosaic vessels, lined partially by VM-engaging tumor cells, bona fide vascular endothelial cells, or CSC-
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Targeting CD133 in Cancer Treatment derived endothelium. The formation of such an intricate vascular niche is, at least in part, dependent on the CD133þ subset within the tumor, which comprises not only the CD133þ CSCs but also the CD133þ EPCs. For example, CD133þ endothelial stem and progenitor cells (EPCs) can be recruited for angiogenesis or vasculogenesis of the tumor, and CD133þ CSCs have been shown to secrete proangiogenic factors, as well as to differentiate into vascular cells and VM channels. More importantly, reciprocal signaling between CD133þ CSCs and niche-associated ECM, endothelium, and their precursors (EPCs) is not only pivotal in maintaining existing CSCs, but may induce stem cell phenotype in the differentiated tumor populations. Thus, therapeutic approaches aiming at CD133 targeting may deliver multipronged effects by directly targeting the CD133þ CSC population and disturbing their niches via inhibition of diverse angiogenic forms as well as VM. Regardless of the overwhelming evidence supporting an essential role for CD133 in tumor vasculature and niche morphogenesis, the underlying mechanisms that govern its multifaceted function require further elucidation. For example, despite sharing a role in the VEGF pathway, it is unclear what signals control whether CD133þ CSCs differentiate into CD31þ tumor endothelium or CD31 VM channels. Furthermore, the mechanisms downstream of CD133 in establishing the vascular niche and the gradient of microenvironmental signals modulating the CSC phenotype remain unknown. Through a therapeutic perspective, the environmental cues that induce the conversion of CD133 cells to CD133þ CSCs require elucidation and may serve as promising targets for novel niche-dependent therapeutic strategies. As we continue to unveil the complexity of CSCs and their surrounding niches, we are constantly reminded that effective anticancer treatments will require strategic and combined approaches to circumvent tumor plasticity and heterogeneity. CD133-targeted therapy offers a promising multipronged approach, bypassing the cancer stem cell plasticity by disrupting the codependence between the CSCs and their niches.
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