Clonal evolution model strikes back at cancer stem cell hierarchical model in the Head & Neck tumor

Heterogeneity in cancer with hypothesized models has been reviewed in terms of definition and markers 1, 2. This commentary deals with the two models of tumor progression in Head and Neck tumors: the stochastic clonal evolution model versus the cancer stem cell (CSC) hierarchical model. Cameron et al. addressed this controversial issue and reported that heterogeneity of head & neck squamous cell carcinoma (HNSCC) is experimentally explained by the stochastic clonal evolution model 3. The initiation of HNSCC in a xenotransplant model is most consistent with a stochastic clonal evolution model since all the single cells derived from HNSCC cell lines have tumor-initiating activity. In addition, clonal variants derived from tumor cells give rise to microenvironments that support tumor cells. The observations raise an old and new issue, i.e. cancer stem cell model versus clonal evolution model, in the HNSCC as well as other cancers.



Two models in solid tumor

CSC theory was proposed nearly half a century ago. The presence of CSCs was suggested around the same time as when hematopoietic stem cells were found. According to the CSC model, the tumor is viewed as an entity that can be studied applying the principles of stem cell biology. Stem cells have been identified in tissues such as bone marrow, brain, intestine, and skin, and tissue structure is generated by hierarchical stem cell systems. Similarly, a hierarchical organization consisting of a CSC at the top of the hierarchy exists in cancer tissues, similar to stem cell systems of normal tissues, and a small number of CSCs maintain cancer tissue by supplying tumor cells. In 1963 it was reported that only 1 to 4% of murine lymphoma cells formed colonies in the spleen, and 0.02 to 0.1% of solid tumor cells formed colonies 4. Very low populations of human leukemic cells generated acute myeloid leukemia in NOD/Scid mice 5. Marker analysis revealed that CD34-positive and CD38-negative fractions had leukemogenic capacity. These inspiring reports suggest that leukemic cells have a hierarchical system with CSCs at the top, like intact hematopoiesis. In contrast, the stochastic clonal evolution model is that all cells of the tumor have equal ability to propagate the tumor. Most tumors are largely composed of cells with some degree of differentiation, based on which tissue of origin can be determined. This morphological heterogeneity is explained by aberrant differentiation pathways due to genetic and/or epigenetic instability of the tumor cells. Comparing the two models in the context of continuing mutations and selective pressure, the two models may not be very different.



Clonal evolution model re-visited in HNSCC

The definition of a CSC is a cell within a tumor that possesses the capacity to self-renew and to cause the heterogeneous lineages of cancer cells that comprise the tumor. CSCs can thus only be defined experimentally by their ability to recapitulate the generation of a continuously growing tumor 6. As is the CSC model of hematopoietic malignancies, the xenotransplantation model, cell surface analysis, and clonal cell analysis have been used to determine which model can explain tumor progression and intratumoral heterogeneity. Cameron et al., indeed, employed these methods to examine the biologic basis for tumor initiation of HNSCC 3. Self-renewal capability of CSCs can be assessed by a colony- forming assay and tumor formation in irradiated mice and/or immunodeficient mice. Implantation into immunodeficient mice is the most reliable method; however, there are biological constraints which make the interpretation of the xenotransplantation assay difficult. The result is biased by the process of tumor cell homing and successful engraftment. Poor tumor initiation can also be explained by post-transplant loss of the implanted cells. In Cameron’s paper, tracing by GFP labeling of implanted cells eliminated the possibility of post-transplant loss in vivo 3.



Isolation of a subpopulation of tumor cells with stem cell-like features and tumorigenic capabilities results in formation of many solid tumors. To identify CSCs in solid tumors, tumor cells are fractionated by cell surface markers, and implanted into immunodeficient mice to assess xenograft growth and cellular composition. Cell surface molecules such as CD24, CD44, and CD133 have been analyzed for CSC markers. CD24-low/negative CD44-positive fractions of breast cancers have significantly higher tumorigenic potential in immunodeficient mice 7 and in a single tissue section of primary uncultured human breast tumors 8. CSCs in the brain tumor are identified by isolation with CD133 marker and the side population 9. These studies are followed by similar findings in a wide variety of tumors originated from prostate, colon, pancreas, liver, and melanocytes 10-13. In addition to cell surface markers, aldehyde dehydrogenase 1A1 and cystatin E/M are suggested as a CSC marker of the prostate and a non-cancer cell marker of the brain, respectively 14, 15. Controversial results are reported in brain tumors: both CD133-positive and –negative populations have CSC properties 16. In HNSCC, a CD44-positive population is reported to possess CSC properties 17. On the contrary, the article in this issue reports that no correlation was observed between the expression of specific markers (CD44, CD133, side population) and cells with tumor-initiating activities 3, implying the clonal evolution model in HNSCC.



The controversial results may be in part due to the limitation of the experimental approaches to determine the model. Isolation of CSCs, especially from solid tumors, is relatively difficult, and can be done only by flow cytometric sorting using antibodies. Instead of tumor tissues, Cameron et al. used cell lines and subcloned cells from a single cell. Single cell clones randomly isolated from HNSCC cell lines are all capable of initiating tumors after implantation into mice (Cameron et al.’s paper of this issue, Table II) 3. This result explains the clonal evolution model of HNSCC; however, implanted cells (3 x 103 to 1 x 106) were propagated in vitro after subcloning. This subcloning process includes the possibility for selection of tumor cells with tumor-initiating activity and elimination of tumor cells without it. Thus, experiments with cell lines in combination with the xenotransplantation assay cannot simply be interpreted. Furthermore, tumor initiation in xenotransplantation models of HNSCC is inefficient, and this assessment takes 3 to 6 months after implantation. To clearly determine the model, these methodological difficulties also need to be overcome in the future.



Niche cells derived from tumor cells

Interactions of tumor cells with their microenvironment can lead to altered growth and differentiation. The phenotypic plasticity of tumor cells suggests that dynamic equilibrium exits between CSCs and non-CSCs, depending on signals from the microenvironment 18. Leukemic stem cells express CD44 at a high level, and antibody therapy is developed, based on the CD44-mediated interaction between cancer cells and their microenvironment 19, 20. Anti-CD44 antibody inhibits homing/engraftment of leukemic stem cells, but not that of hematopoietic stem cells. Similarly, engraftment of solid tumors may be affected by CD44 on the supporting cells (microenvironment), and CD44 is indeed a cell surface marker for CSCs of solid tumors such as breast cancer.



Interactions of stromal cells with tumor cells include growth stimulation, angiogenesis and immunocompetence. In this point of view, tumor cells imitate normal tissues where stromal cells support tissue stem cells. These stromal cells can also be differentiated from tumor cells. Clonal variants-derived tumor cells act as stromal-supporting cells and modulate overall initiating activity (Fig. 1). Cameron et al. proposed that this tumor microenvironment is generated by the heterogeneous population of tumor cells in combination with the clonal evolution model in HNSCC 3. The opposing idea is that heterogeneity of tumor cells generates a microenvironment: clonal variants induce varying degrees of angiogenesis through different levels of cytokines such as vascular endothelial growth factor produced from tumor cells 21.



Although the experiments by Cameron et al. were performed by using cell lines and their single cell-derived subclones, the study on the clonal evolution model of HNSCC should be highly evaluated because the old and new issue needs to be solved in each cancer from the viewpoint of therapy. These two models are conceptually essential to treat cancer in a different way. CSCs are the only target for anti-cancerous therapy in the CSC model. In contrast, all the cells are necessarily killed by anti-cancerous therapy in the clonal evolution model because all will be equally able to cause a relapse after therapy. Analysis on primary uncultured HNSCC cells with the same approach will be necessary in the future to determine which model is most consistent.



REFERENCES



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3 Cameron S, Dahler A, Endo-Munoz L, et al. Tumour initiating activity and tumour morphology of HNSCC is modulated by interactions between clonal variants within the tumour. Lab Invest;this issue.



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9 Singh SK, Clarke ID, Terasaki M, et al. Identification of a cancer stem cell in human brain tumors. Cancer Res 2003;63(18):5821-5828.



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12 Ricci-Vitiani L, Lombardi DG, Pilozzi E, et al. Identification and expansion of human colon-cancer-initiating cells. Nature 2007;445(7123):111-115.



13 Li C, Heidt DG, Dalerba P, et al. Identification of pancreatic cancer stem cells. Cancer Res 2007;67(3):1030-1037.



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Clonal evolution model strikes back at cancer stem cell hierarchical model in the Head & Neck tumor

The two models of tumor progression in head and neck squamous cell carcinoma are proposed: stochastic clonal evolution model and cancer stem hierarchy model. Cell surface marker analysis and clonal cell analysis in combination with a xenotransplant approach have been performed to determine the model, but the interpretation is sometimes difficult due to multiple biological parameters and the stromal environment permissive to tumor growth. Understanding of which model is most applicable to head and neck squamous cell carcinoma as well as other cancers should be further promoted because it suggests differential approaches in treatment.

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Alternative lengthening of telomeres (ALT)

Nature. 2010 Apr 8;464(7290):858-63. Epub 2010 Mar 24.
Zscan4 regulates telomere elongation and genomic stability in ES cells.
Zalzman M, Falco G, Sharova LV, Nishiyama A, Thomas M, Lee SL, Stagg CA, Hoang HG, Yang HT, Indig FE, Wersto RP, Ko MS.

Developmental Genomics and Aging Section, Laboratory of Genetics, NIH, Baltimore, Maryland 21224, USA
Abstract
Exceptional genomic stability is one of the hallmarks of mouse embryonic stem (ES) cells. However, the genes contributing to this stability remain obscure. We previously identified Zscan4 as a specific marker for two-cell embryo and ES cells. Here we show that Zscan4 is involved in telomere maintenance and long-term genomic stability in ES cells. Only 5% of ES cells express Zscan4 at a given time, but nearly all ES cells activate Zscan4 at least once during nine passages. The transient Zscan4-positive state is associated with rapid telomere extension by telomere recombination and upregulation of meiosis-specific homologous recombination genes, which encode proteins that are colocalized with ZSCAN4 on telomeres. Furthermore, Zscan4 knockdown shortens telomeres, increases karyotype abnormalities and spontaneous sister chromatid exchange, and slows down cell proliferation until reaching crisis by passage eight. Together, our data show a unique mode of genome maintenance in ES cells.
PMID: 20336070



Genes Cells. 2006 Nov;11(11):1305-15.
Rad54 is dispensable for the ALT pathway.
Akiyama K, Yusa K, Hashimoto H, Poonepalli A, Hande MP, Kakazu N, Takeda J, Tachibana M, Shinkai Y.
Department of Life Science, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.
Abstract
Some immortal cells use the alternative lengthening of telomeres (ALT) pathway to maintain their telomeres instead of telomerase. Previous studies revealed that homologous recombination (HR) contributes to the ALT pathway. To further elucidate molecular mechanisms, we inactivated Rad54 involved in HR, in mouse ALT embryonic stem (ES) cells. Although Rad54-deficient ALT ES cells showed radiosensitivity in line with expectation, cell growth and telomeres were maintained for more than 200 cell divisions. Furthermore, although MMC-stimulated sister chromatid exchange (SCE) was suppressed in the Rad54-deficient ALT ES cells, ALT-associated telomere SCE was not affected. This is the first genetic evidence that mouse Rad54 is dispensable for the ALT pathway.
PMID: 17054727


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Controversial reports on spontaneous transformation of MSCs

・Points to Consider in the Characterization of Cell Lines Used to Produce Biologicals 7/12/1993
http://www.fda.gov/cber/gdlns/ptccell.pdf


Spontaneous malignant transformation of human mesenchymal stem cells reflects cross-contamination: putting the research field on track - letter.
Torsvik A, R?sland GV, Svendsen A, Molven A, Immervoll H, McCormack E, L?nning PE, Primon M, Sobala E, Tonn JC, Goldbrunner R, Schichor C, Mysliwietz J, Lah TT, Motaln H, Knappskog S, Bjerkvig R.
Cancer Res. 2010 Aug 1;70(15):6393-6.

Deficiency in p53 but not retinoblastoma induces the transformation of mesenchymal stem cells in vitro and initiates leiomyosarcoma in vivo.
Rubio R, Garc?a-Castro J, Guti?rrez-Aranda I, Paramio J, Santos M, Catalina P, Leone PE, Menendez P, Rodr?guez R.
Cancer Res. 2010 May 15;70(10):4185-94.



Long-term cultures of bone marrow-derived human mesenchymal stem cells frequently undergo spontaneous malignant transformation.
R?sland GV, Svendsen A, Torsvik A, Sobala E, McCormack E, Immervoll H, Mysliwietz J, Tonn JC, Goldbrunner R, L?nning PE, Bjerkvig R, Schichor C.
Cancer Res. 2009 Jul 1;69(13):5331-9.

Cancer Res. 2005 Apr 15;65(8):3035-9.
Spontaneous human adult stem cell transformation.
Rubio D, Garcia-Castro J, Mart?n MC, de la Fuente R, Cigudosa JC, Lloyd AC, Bernad A.

Department of Immunology and Oncology, Centro Nacional de Biotecnolog?a/Consejo Superior de Investigaciones Cientificas, UAM Campus de Cantoblanco, Darwin, 3 E-28049 Madrid, Spain.
Erratum in:

Cancer Res. 2005 Jun 1;65(11):4969.
Comment in:
Cancer Res. 2005 Oct 15;65(20):9601; author reply 9601.
Abstract
Human adult stem cells are being evaluated widely for various therapeutic approaches. Several recent clinical trials have reported their safety, showing them to be highly resistant to transformation. The clear similarities between stem cell and cancer stem cell genetic programs are nonetheless the basis of a recent proposal that some cancer stem cells could derive from human adult stem cells. Here we show that although they can be managed safely during the standard ex vivo expansion period (6-8 weeks), human mesenchymal stem cells can undergo spontaneous transformation following long-term in vitro culture (4-5 months). This is the first report of spontaneous transformation of human adult stem cells, supporting the hypothesis of cancer stem cell origin. Our findings indicate the importance of biosafety studies of mesenchymal stem cell biology to efficiently exploit their full clinical therapeutic potential.


Human bone marrow derived mesenchymal stem cells do not undergo transformation after long-term in vitro culture and do not exhibit telomere maintenance mechanisms.
Bernardo ME, Zaffaroni N, Novara F, Cometa AM, Avanzini MA, Moretta A, Montagna D, Maccario R, Villa R, Daidone MG, Zuffardi O, Locatelli F.
Cancer Res. 2007 Oct 1;67(19):9142-9.


Human bone marrow derived mesenchymal stem cells do not undergo transformation after long-term in vitro culture and do not exhibit telomere maintenance mechanisms.
Bernardo ME, Zaffaroni N, Novara F, Cometa AM, Avanzini MA, Moretta A, Montagna D, Maccario R, Villa R, Daidone MG, Zuffardi O, Locatelli F.
Cancer Res. 2007 Oct 1;67(19):9142-9.
PMID: 17909019

Greetings Presentation example

Good morning, ladies and gentlemen.

Thank you for taking time out of your schedules to attend this session. My name is xxx and I am xxx of the NCCHD. NCCHD is a government-related organization that works to promote medicine, especially in the field of pediatrics and obstetrics in Japan and other countries. Our activities include facilitating foreign direct investment into Japan, helping the international xxx of Japan’s small and medium-sized firms, enhancing Japan’s xxx with developing countries and, organizing seminars to encourage international business in high-tech areas. I am delighted that NCCHD has the opportunity to introduce Japan’s cell-based therapy.

We have selected glycoscience as the topic for today’s session. There are several reasons.

Firstly, glycoscience is a cutting-edge life sciences field that has enormous potential for various applications. As you know, glycan microarrays and glycan biomarker provide unique and powerful tools for the development of cancer diagnosis and therapy, as well as regenerative medicine and stem cell-based therapy. There are high expectations for the development of new drugs and practical applications for innovative medicines using these tools.

Secondly, we chose glycoscience because Japan is a pioneer in this key field. The country accounted for xx% of the world’s glycoscience-related patent applications between 20xx and 20xx; this is behind only the Uxx, which accounted for xx% of all applications. Japanese firms have been contributing to the development of innovative medicine using glycoscience. For example, this March, xxx received a exclusive license from xxx, for a therapeutic antibody developed using xxx’s unique glycoscience technology,“xxx”.

Last but not least, glycoscience is an area where we would like to foster and support international tie-ups and collaboration. At this year’s xxx, xx Japanese companies and organizations are exhibiting at the Japan xxx. They present technology and products in the area of glycoscience, including cell engineering, regenerative medicines, microarray and nano-biotech. International collaboration is crucial for high-tech researches, and I hope today’s session will lead you to new opportunities, such as joint research and technology alliances with Japanese exhibitors. We look forward to welcoming all of you to the Japan xxx3.

To conclude, I hope that today’s session will be highly informative on the latest trends in the development and application of glycoscience, and in some way be helpful for your business with Japan in the future.

Thank you.