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Ward WH, Farma JM, editors. Cutaneous Melanoma: Etiology and Therapy [Internet]. Brisbane (AU): Codon Publications; 2017 Dec 21. doi: 10.15586/codon.cutaneousmelanoma.2017.ch4
Abstract
The heterogeneity and plasticity of aggressive melanoma presents formidable challenges in the design of current therapies. Plasticity is defined as the phenotype of cancer cells expressing properties normally related to stem cells, including the expression of genes associated with multiple cellular phenotypes and appearing as undifferentiated, embryonic-like cells. The multipotent phenotype of these tumor cells, expressing vascular, embryonic, and cancer stem cell (CSC) capabilities, offers new insights into their functional adaptation and resistance to current therapies. This chapter highlights major advances in research that (i) help clarify the underlying challenges associated with angiogenesis inhibitor therapy; (ii) discuss important implications of the discovery of reactivation of the normally dormant Nodal embryonic signaling pathway that underlies the CSC phenotype, unregulated tumor growth and metastasis, and resistance to current therapies; and (iii) demonstrate the advantage of using combinatorial strategies to effectively target heterogeneous melanoma subpopulations to eliminate relapse and disease progression.
Key words:
Chemoresistance, Heterogeneity, Melanoma, Nodal, PlasticityIntroduction
Tumor heterogeneity presents a significant conundrum pertinent to the design of effective therapeutic approaches that mitigate residual disease and progression to metastasis. The complexity of this issue has not been fully appreciated until the dawn of genomic analysis and the revelation of various subpopulations of tumor cells within a tumor lesion expressing multiple phenotype-specific genes and diverse protein markers, especially prevalent in aggressive melanoma (1). At first, these findings seemed enigmatic; however, they prompted further experimental studies into the biological and clinical relevance of a multi-potent or plastic tumor cell phenotype. Most noteworthy, patients with metastatic disease were relapsing following conventional therapies, which strongly suggested the critical need for a refocused approach utilizing targeted therapies.
After years of clinical trials, preventive sunscreen advocacy, and personalized targeted therapies, metastatic melanoma remains the most aggressive and deadly type of skin cancer. In advanced-state metastatic disease, the latest statistics reveal a median overall survival of less than 6 months (2). FDA-approved agents have included a spectrum of products ranging from conventional chemotherapy such as dacarbazine (DTIC) (3), to ipilimumab—a monoclonal antibody that targets the regulatory checkpoint CTLA-4 in T-cells (4), in addition to inhibitors of mutationally activated BRAF (BRAFi) (5, 6), which have been used in combination with trametinib, an inhibitor of the mitogen-activated, extracellular signal–regulated kinase inhibitor (MEK) (7). Additional therapeutic approaches have recently included agents that target the programmed death 1 pathway (8). Despite these noteworthy advances in treatment strategies, an urgent clinical need remains to achieve improved progression-free and overall survival. However, one of the most difficult challenges to address is cellular heterogeneity within aggressive tumors, as depicted in Figure 1. First-line therapies can target portions of a primary tumor, but residual disease can arise from subpopulations of cancer cells with stem cell properties. Metastatic disease can arise from the expansion of cancer stem cells (CSCs) with drug resistance properties, which are not targeted by current therapies. Acquiring a better understanding of the molecular underpinnings of the subpopulations that express a plastic phenotype—and may appear as vascular and embryonic in nature—will lead to the development of new cancer interventions.
Melanoma Vascular Phenotype
The pioneering work of Dr Judah Folkman with respect to tumor angiogenesis initiated a critical paradigm for strategically targeting the blood supply to tumors, and guided the pharmaceutical industry to develop antiangiogenesis agents with the goal of inhibiting growth through nutrient starvation (9). However, as disappointment grew over the outcomes of angiogenesis inhibitor clinical trials, researchers took a closer look at the molecular signature of tumor cells that appeared resistant to this new class of agents. In the case of melanoma, there was confounding molecular evidence, indicating that aggressive melanoma cells express multiple cellular phenotypes, including those closely associated with endothelial cells, epithelial cells, and stem cells—suggesting an unusual plasticity with uncertain significance (1, 10). From a purely scientific perspective, these results were fascinating at the time but fostered serious questions and concerns about cell-type-specific markers that were used to characterize tumor cells versus normal cells. Essentially, depending on the marker selected, melanoma cells could masquerade as endothelial cells because both cell types express endothelial-specific proteins. Most noteworthy, during histopathology examination, tumor cells could be underestimated or at worst go undetected.
When the functional relevance of vascular markers was tested in melanoma models, this resulted in the surprising observation that aggressive melanoma cells expressing endothelial markers can form de novo, perfusable, vasculogenic-like networks in three-dimensional culture (3-D), which we named vasculogenic or vascular mimicry (11, 12). Ultrastructural analysis of these networks revealed a remarkable similarity between tumor cell–formed vessels versus endothelial lined vessels, with the exception of the basement membrane lining (13). In tumor cell– formed vessels, blood passes through basement membrane–lined vascular networks with tumor cells sitting exterior to the membrane matrix, while traditional vessels support blood flowing through endothelial cells lining the vasculature with the basement membrane exterior to the cells. The light microscopic morphological characterization of VM in patient tumors showed matrix-rich channels containing plasma and RBCs lined by melanoma cells, and noteworthy poor clinical outcome in patients where VM was identified (14). Because VM is associated with the aggressive tumor cell phenotype and advanced stage disease, it is hypothesized that this extravascular perfusion pathway serves as a growth advantage and escape route for rapidly growing tumor cells.
When the concept of VM was first presented, it was considered quite controversial (15, 16). However, with the persistent lack of success of angiogenesis inhibitors, the VM paradigm received a serious, second look. Particularly noteworthy was the critical experiment conducted by our laboratory and collaborators, which consisted of a side-by-side comparative analysis of the effects of endostatin (a classical angiogenesis inhibitor) on endothelial cell formation of angiogenic networks versus melanoma cell–formed VM networks (17). In this straightforward experiment using 3-D cultures, the data revealed the inhibitory effect of endostatin on angiogenesis as expected, but melanoma VM was unaffected. This observation prompted further assessment of the underlying molecular mechanisms that might help explain the noteworthy differential response. We chose to specifically measure the integrin α5-subunit (the endostatin target) expression in human endothelial cells and human metastatic melanoma cells, and found a high level of integrin α5-subunit expressed (at the gene and protein levels) by endothelial cells and little to no expression of this endostatin target by melanoma tumor cells.
These results provided a substantial explanation for the failure of angiogenesis inhibitors in targeting tumors containing VM pathways, especially prominent in aggressive disease states. Shortly after this revelation, VM was officially adopted as one of the vascular supply routes contributing to the tumor vasculature (18), which would eventually prompt the design of more rational, targeted vascular disrupting agents. This strategic approach was further informed by microgenomics studies conducted by our laboratory consisting of a comparative molecular analysis of laser capture microdissected networks formed during angiogenesis versus melanoma VM (19). These findings revealed factors contributing to tumor plasticity, in addition to documenting important differences and similarities in angiogenesis compared with VM, especially the heterogeneous subpopulations engaged in various aspects of VM. Most noteworthy, new targets for vascular disruption were discovered in this study, which supported the development for a new class of agents.
Melanoma Embryonic Phenotype
The microgenomics study contributed valuable insights into the key players responsible for VM functionality and also introduced a new avenue of investigation in our laboratory focused on understanding the implications of the embryonic phenotype of melanoma, which feature prominently in sustaining plasticity. This direction was also supported by developmental biology findings showing that cytotrophoblasts engage in VM during the formation of the placenta (20), and accentuated the notion that tumors can recapitulate early developmental events. To gain a broader perspective of the melanoma embryonic phenotype, a molecular comparative analysis was performed on human embryonic stem cells (hESCs) and human melanoma cells expressing the aggressive, multipotent phenotype. These studies revealed the robust expression of a Nodal embryonic signaling pathway in melanoma cells, which was present in the aggressive phenotype but not in the nonaggressive phenotype (21, 22).
Since this was the first description of Nodal in cancer, we searched the literature for information pertaining to its possible function and found the primary resource to be developmental studies (23). Nodal is a powerful embryonic morphogen belonging to the TGF-beta superfamily. It is critical in the maintenance of hESC pluripotency, as well as axis formation and L-R patterning. Nodal can act in an autocrine and paracrine manner, and is largely restricted to embryonic tissues and mostly lost in normal tissues. While hESCs and aggressive, multipotent melanoma cells share Nodal expression in common, only hESCs express the natural inhibitor of Nodal—called Lefty, also a member of the TGF-beta superfamily. Our findings revealed that while Nodal is reactivated in aggressive tumor cells, Lefty is mostly silenced through methylation (24). These observations gave us additional clues relevant to aggressive melanoma cells and the underlying embryonic phenotype. We postulated, and then confirmed, that Nodal expression contributes to the growth of melanoma tumors, and this embryonic signaling pathway is unregulated due to the absence of Lefty, allowing uncontrolled proliferation (22). We also hypothesized that Nodal is a master plasticity gene, based on its quintessential role in hESCs, and we tested this theory by downregulating Nodal expression in melanoma cells and observed a direct impact on phenotype. Specifically, when the melanoma cells no longer expressed Nodal, they acquired a more normal melanocytic phenotype, down-regulated their vascular phenotype, were unable to engage in VM, and had a diminished capacity to form tumors (21).
The translational relevance of the Nodal finding was further validated by our laboratory and others using patient tissues and immunohistochemistry (IHC) analyses. Nodal was found to be associated with advanced stages of melanoma, breast, prostate, pancreatic, ovarian and colon cancer, in addition to glioblastoma and neuroblastoma (25). Collectively, these results supported the potential of Nodal as a valuable prognostic biomarker and promising new target to inhibit tumorigenicity and metastasis (26). To pursue this concept, we tested the effects of anti-Nodal antibody therapy on melanoma mouse models injected with metastatic tumor cells. The results showed a reduction in tumor growth at the primary site of orthotopic injection, and a reduction in lung tumor burden in the experimental metastasis model (25, 27, 28). Although these studies were promising, this approach using monotherapy to target only Nodal-expressing melanoma cells did not completely inhibit tumor formation. These data, together with FACS analyses revealing only a minor percentage of melanoma cells actually express Nodal, persuaded us to reevaluate our approach to effectively target aggressive melanoma, which led us to more carefully consider the CSC phenotype in subpopulations of melanoma.
Cancer Stem Cell Phenotype
Guided by the implications of CSCs, as illustrated in Figure 1, expanding their influence during tumor progression because they are able to survive current therapies, we hypothesized that the melanoma cells expressing Nodal would also express a well-characterized CSC marker, CD133, also associated with drug resistance (29). We employed SmartFlare™ technology to selectively sort and study the functional relevance of Nodal subpopulations existing within heterogeneous melanoma cell lines (30). The results indicated that melanoma subpopulations selected for Nodal expression concomitantly expressed CD133 and displayed significant tumorigenic growth in soft agar compared with nonselected cells.
These experiments stimulated a line of inquiry specifically focused on the question of whether current therapies for metastatic melanoma patients were targeting Nodal. Starting with dacarbazine (DTIC), FDA approved in the 1970s, we discovered that the residual tumor cells surviving treatment are strongly Nodal-positive (31). However, a combinatorial approach of treating with DTIC followed by anti-Nodal antibody treatment was most effective in causing cell death, accompanied by the expression of cleaved PARP (an apoptosis marker). Further support for the critical need of new therapeutic approaches, also revealed in this study, showed prominent IHC Nodal localization in patient tissues before and after DTIC treatment. Despite DTIC failing for most patients, it is still used as the frontline therapy in many cases.
Melanoma patients, like many others with cancer, could benefit from targeted therapies as part of the era of personalized medicine. However, despite advances in the field, the heterogeneity of melanoma—especially the CSC subpopulations expressing Nodal and drug resistance markers—complicate our ability to mitigate relapse and progression to metastasis with current therapeutic options. To address this clinical challenge, our laboratory and collaborators examined whether melanoma patients treated with BRAFi therapy experienced a change in the Nodal-expressing tumor cells. The results showed that BRAFi treatment failed to affect Nodal levels in matched melanoma patient samples before and after therapy— that preceded their eventual death due to disease (32). These data encouraged us to perform an experimental assessment using a mouse model with tagged human metastatic melanoma cells, comparing groups treated with monotherapies of BRAFi or anti-Nodal mAb or a combination of both versus controls. The results clearly demonstrated the efficacy of using the combinatorial approach of BRAFi plus anti-Nodal mAb, compared with monotherapy and control. These data provide a promising new strategic approach using front-line therapy together with targeting a CSC-associated molecule—Nodal.
Conclusion
The heterogeneity and plasticity of aggressive melanoma present formidable challenges in the design of current therapies. However, recognizing that cancer cells can reactivate normally dormant embryonic pathways to exacerbate tumorigenicity and metastasis may present a unique therapeutic opportunity. The multipotent phenotype of aggressive melanoma cells—with vascular, embryonic, and CSC capabilities—offers new insights into their functional adaptation and resistance to current therapies. Considering that aggressive tumors utilize multiple mechanisms to survive and metastasize, it seems prudent to use evidence-based reports to develop combinatorial strategies to effectively target heterogeneous melanoma subpopulations—to eliminate relapse and disease progression.
Acknowledgment: Supported by the National Institute of General Medical Sciences U54GM104942 (REBS, EAS, NVM) and NIH/NCI R37CA59702 and RO1CA121205 (MJCH).
Conflict of interest: The authors declare no potential conflicts of interest with respect to research, authorship, and/or publication of this article.
Copyright and permission statement: To the best of our knowledge, the materials included in this chapter do not violate copyright laws. All original sources have been appropriately acknowledged and/or referenced. Where relevant, appropriate permissions have been obtained from the original copyright holder(s).
References
- 1.
- Bittner M, Meltzer P, Chen Y, Jiang Y, Seftor E, Hendrix MJC, et al. Molecular classification of cutaneous malignant melanoma by gene expression profiling. Nature. 2000 Aug 3;406(6795):536–40. [PubMed: 10952317] [CrossRef]
- 2.
- Song X, Zhao Z, Barber B, Farr AM, Ivanov B, Novish M. Overall survival in patients with metastatic melanoma. Curr Med Res Opin. 2015 May;31(5):987–91. [PubMed: 25708472] [CrossRef]
- 3.
- Gogas HJ, Kirkwood JM, Sondak VK. Chemotherapy for metastatic melanoma: Time for a change. Cancer. 2007 Feb 1;109:455–64. [PubMed: 17200963] [CrossRef]
- 4.
- Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010 Aug 19;363:711–23. [PMC free article: PMC3549297] [PubMed: 20525992] [CrossRef]
- 5.
- Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011 Jun 30;364:2507–16. [PMC free article: PMC3549296] [PubMed: 21639808] [CrossRef]
- 6.
- Ascierto PA, Minor D, Ribas A, Lebbe C, O’Hagan A, Arya N, et al. Phase II trial (BREAK-2) of the BRAF inhibitor dabrafenib (GSK2118436) in patients with metastatic melanoma. J Clin Oncol. 2013 Sept 10;31:3205–11. [PubMed: 23918947] [CrossRef]
- 7.
- Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012 Jul 12;367:107–14. [PubMed: 22663011] [CrossRef]
- 8.
- Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of PD-1 antibody in cancer. N Engl J Med. 2012 Jun 28;366:2443–54. [PMC free article: PMC3544539] [PubMed: 22658127] [CrossRef]
- 9.
- Folkman J. Seminars in Medicine of the Beth Israel Hospital, Boston. Clinical applications of research on angiogenesis. N Engl J Med. 1995 Dec 28;333:1757–63. [PubMed: 7491141] [CrossRef]
- 10.
- Seftor EA, Meltzer PS, Schatteman GC, Gruman LM, Hess AR, Kirschmann DA, et al. Expression of multiple molecular phenotypes by aggressive melanoma tumor cells: Role in vasculogenic mimicry. Crit Rev Oncol Hematol. 2002 Oct;44:12–27. [PubMed: 12398997] [CrossRef]
- 11.
- Hendrix MJC, Seftor EA, Meltzer PS, Gardner LM, Hess AR, Kirschmann DA, et al. Expression and functional significance of VE-cadherin in aggressive human melanoma cells: Role in vasculogenic mimicry. Proc Natl Acad Sci U S A. 2001 Jul 3;98:8018–23. [PMC free article: PMC35460] [PubMed: 11416160] [CrossRef]
- 12.
- Hendrix MJC, Seftor EA, Hess AR, Seftor REB. Vasculogenic mimicry and tumour-cell plasticity: Lessons from melanoma. Nat Rev Cancer. 2003 Jun;3(6):411–21. [PubMed: 12778131] [CrossRef]
- 13.
- Seftor REB, Hess AR, Seftor EA, Kirschmann DA, Hardy KM, Margaryan NV, et al. Tumor cell vasculogenic mimicry: From controversy to therapeutic promise. Am J Pathol. 2012 Oct;181(4):1115–25. [PMC free article: PMC4851740] [PubMed: 22944600] [CrossRef]
- 14.
- Yang JP, Liao YD, Mai DM, Xie P, Qiang YY, Sheng LS, et al. Tumor vasculogenic mimicry predicts poor prognosis in cancer patients: A meta-analysis. Angiogenesis. 2015 Oct 25;19:191–200. [PubMed: 26899730] [CrossRef]
- 15.
- Maniotis AJ, Folberg R, Hess AR, Seftor EA, Gardner LM, Pe’er J, et al. Vascular channel formation by human melanoma cells in vivo and in vitro: Vasculogenic mimicry. Am J Path. 1999 Sept;155(3):739–52. [PMC free article: PMC1866899] [PubMed: 10487832] [CrossRef]
- 16.
- McDonald DM, Munn L, Jain RK. Vasculogenic mimicry: How convincing, how novel, and how significant? Am J Pathol. 2000 Feb;156(2):383–8. [PMC free article: PMC1850027] [PubMed: 10666365] [CrossRef]
- 17.
- Van de Schaft D, Seftor REB, Seftor EA, Hess AR, Gruman LM, Kirschmann DA, et al. Effects of angiogenesis inhibitors on vascular network formation by human endothelial and melanoma cells. J Natl Cancer Inst. 2004 Oct 6;96(19):1473–77. [PubMed: 15467037] [CrossRef]
- 18.
- Fidler IJ, Ellis LM. Neoplastic angiogenesis—Not all blood vessels are created equal. N Engl J Med. 2004 Jul 15;351:215–16. [PubMed: 15254281] [CrossRef]
- 19.
- Demou ZN, Hendrix MJC. Microgenomics profile the endogeneous angiogenic phenotype in subpopulations of aggressive melanoma. J Cell Biochem. 2008 Oct 1;105:562–73. [PMC free article: PMC2654186] [PubMed: 18655191] [CrossRef]
- 20.
- Zhou Y, Fisher SJ, Janatpour M, Genbacev O, Dejana E, Wheelock M, et al. Human cytotrophoblasts adopt a vascular phenotype as they differentiate. J Clin Invest. 1997 May;99(9):2139–51. [PMC free article: PMC508044] [PubMed: 9151786] [CrossRef]
- 21.
- Topczewska JM, Postovit LM, Margaryan NV, Sam A, Hess AR, Wheaton WW, et al. Embryonic and tumorigenic pathways converge via Nodal signaling: Role in melanoma aggressiveness. Nature Med. 2006 Aug;12(8):925–32. [PubMed: 16892036] [CrossRef]
- 22.
- Postovit LM, Margaryan NV, Seftor EA, Kirschmann DA, Lipavsky A, Wheaton WW, et al. Human embryonic stem cell microenvironment suppresses the tumorigenic phenotype of aggressive cells. Proc Natl Acad Sci U S A. 2008 Mar 18;105(11):4329–34. [PMC free article: PMC2393795] [PubMed: 18334633] [CrossRef]
- 23.
- Schier AF. Nodal signaling in vertebrate development. Annu Rev Cell Dev Biol. 2003;19:589–621. [PubMed: 14570583] [CrossRef]
- 24.
- Costa FF, Seftor EA, Bischof JM, Kirschmann DA, Strizzi L, Arndt K, et al. Epigenetically reprogramming metastatic tumor cells with an embryonic microenvironment. Epigenomics. 2009 Dec;1(2):387–98. [PMC free article: PMC2872497] [PubMed: 20495621] [CrossRef]
- 25.
- Strizzi L, Sandomenico A, Margaryan NV, Foca A, Sanguigno L, Bodenstine TM, et al. Effects of a novel Nodal-targeting monoclonal antibody in melanoma. Oncotarget. 2015 Oct 9;6(33):34071–86. [PMC free article: PMC4741437] [PubMed: 26460952]
- 26.
- Strizzi L, Hardy KM, Margaryan NV, Hillman DW, Seftor EA, Chen B, et al. Potential for the embryonic morphogen Nodal as a prognostic and predictive biomarker in breast cancer. Breast Cancer Res. 2012 May 11;14(3):R75. [PMC free article: PMC3446338] [PubMed: 22577960] [CrossRef]
- 27.
- Foca A, Sanguigno L, Foca G, Strizzi L, Iannitti R, Palumbo R, et al. New anti-Nodal monoclonal antibodies targeting the Nodal pre-helix loop involved in Cripto-1 binding. Int J Mol Sci. 2015 Sep 7;16(9):21342–62. [PMC free article: PMC4613256] [PubMed: 26370966] [CrossRef]
- 28.
- Strizzi L, Postovit LM, Margaryan NV, Lipavsky A, Gadiot J, Blank C, et al. Nodal as a biomarker for melanoma progression and a new therapeutic target for clinical intervention. Expert Rev Dermatol. 2009;4(1):67–78. [PMC free article: PMC2682534] [PubMed: 19885369] [CrossRef]
- 29.
- Lai CY, Schwartz BE, Hsu MY. CD133+ melanoma subpopulations contribute to perivascular niche morphogenesis and tumorigenicity through vasculogenic mimicry. Cancer Res. 2012 Oct 1;72(19):5111–18. [PMC free article: PMC3463654] [PubMed: 22865455] [CrossRef]
- 30.
- Seftor EA, Seftor REB, Weldon DS, Kirsammer GT, Margaryan NV, Gilgur A, et al. Semin Oncol. 2014 Apr;41(2):259–66. [PMC free article: PMC4026856] [PubMed: 24787297] [CrossRef]
- 31.
- Hardy KM, Strizzi L, Margaryan NV, Gupta K, Murphy GF, Scolyer RA, et al. Targeting Nodal in conjunction with Dacarbazine induces synergistic anticancer effects in metastatic melanoma. Mol Cancer Res. 2015 Apr;13(4):670–80. [PMC free article: PMC4398626] [PubMed: 25767211] [CrossRef]
- 32.
- Hendrix MJC, Kandela I, Mazar AP, Seftor EA, Seftor REB, Margaryan NV, et al. Targeting melanoma with front-line therapy does not abrogate Nodal-expressing tumor cells. Lab Invest. 2017 Feb;97(2):176–86. [PubMed: 27775691] [CrossRef]
- Review Heterogeneity of Melanoma with Stem Cell Properties.[Adv Exp Med Biol. 2019]Review Heterogeneity of Melanoma with Stem Cell Properties.Seftor EA, Margaryan NV, Seftor REB, Hendrix MJC. Adv Exp Med Biol. 2019; 1139:105-114.
- Targeting the Stem Cell Properties of Adult Breast Cancer Cells: Using Combinatorial Strategies to Overcome Drug Resistance.[Curr Mol Biol Rep. 2017]Targeting the Stem Cell Properties of Adult Breast Cancer Cells: Using Combinatorial Strategies to Overcome Drug Resistance.Margaryan NV, Seftor EA, Seftor REB, Hendrix MJC. Curr Mol Biol Rep. 2017 Sep; 3(3):159-164. Epub 2017 Jul 10.
- Review Cancer Stem Cells: Powerful Targets to Improve Current Anticancer Therapeutics.[Stem Cells Int. 2019]Review Cancer Stem Cells: Powerful Targets to Improve Current Anticancer Therapeutics.Bighetti-Trevisan RL, Sousa LO, Castilho RM, Almeida LO. Stem Cells Int. 2019; 2019:9618065. Epub 2019 Nov 12.
- Review Epithelial-to-mesenchymal plasticity of cancer stem cells: therapeutic targets in hepatocellular carcinoma.[J Hematol Oncol. 2016]Review Epithelial-to-mesenchymal plasticity of cancer stem cells: therapeutic targets in hepatocellular carcinoma.Jayachandran A, Dhungel B, Steel JC. J Hematol Oncol. 2016 Aug 30; 9(1):74. Epub 2016 Aug 30.
- Review Cancer stem cell as therapeutic target for melanoma treatment.[Histol Histopathol. 2016]Review Cancer stem cell as therapeutic target for melanoma treatment.Alamodi AA, Eshaq AM, Hassan SY, Al Hmada Y, El Jamal SM, Fothan AM, Arain OM, Hassan SL, Haikel Y, Megahed M, et al. Histol Histopathol. 2016 Dec; 31(12):1291-301. Epub 2016 Jun 15.
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