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Tumor radioresistance and p53: focusing on cancer stem cells
View:219 Time:2016-11-23

                                                                          By D. S. Bautista, Ph.D.
                                                Modecs Genetics, Inc. (Toronto)

The loss of p53 functions, either through mutations on the p53 gene itself or other factors, has long been associated with decreased radiosensitivity of human tumor cells.  For example, patients with recurrent non-small cell lung carcinoma (NSCLC) whose tumors were found with mutations in exons 5-8 of the p53 gene were up to four times less likely to respond to radiotherapy than those patients whose tumors  had wild-type p53.[1]  Similarly, analysis of glioblastoma multiforme brain tumor (GM) clonogenic cell lines has indicated that the lack of functional p53 was associated with resistance to fractionated irradiation.[2] A closer look at the phenomenon suggests that tumor cells that retain radiation-induced G1 arrest and radiation-induced accumulation of p53 levels are those that show the highest sensitivity to ionizing radiation.[3] Simultaneous detection of bcl-2 over-expression and p53 gene mutations in primary squamous-cell carcinoma of the head and neck (HNSCC) treated with conventional radiotherapy is associated with higher risk of locoregional failure and worse survival within 5 years.

Many such examples have pointed to a mechanism whereby tumor cells have become ionizing radiation-resistant because mutations in their p53 fail to induce cell death by apoptosis, or tumor cells have acquired other anti-apoptosis mechanisms such as when bcl-2 is expressed at high levels. As in normal cells, irradiated tumor cells seem to have the choice between dying by apoptosis and undergoing growth arrest, a process that seems to be dictated by the severity of DNA damage, and type of tissue (see review).[4] When tumor cells lose p53 functions, they revert to growth arrest that give the cells a chance to repair DNA damage, and perhaps die by mitotic catastrophe if the damage cannot be repaired.[5] 

The idea that supplementing tumor cells with exogenous p53 by viral vector transduction would increase radiosensitivity, or equivalently, reverse radioresistance, has been tested in both pre-

[1] D. Matsuzoe (2009). P53 mutations predict non-small cell lung carcinoma response to radiotherapy. Cancer Letters 135:189-914.
[2] D. Hass-Kogan, S. Kogan, G. Yount, J. Hsu, M. Haas, D. Deen, and M. Israel (2009). P53 function influences the effect of fractionated radiotherapy on glioblastoma tumors. Intl J Radiation OncoBiologyPhysics 43:399-403.
[3] A.J. McIlwrath, P.A. Vasey, G.M. Ross, and R. Brown (1994). Cell cycle arrests and radiosensitivity of human tumor cell lines: Dependence on wild-type p53 for radiosensitivity. Cancer Research 54:3718-3722.
[4] A.V. Gudkov and E.A. Komarova (2003). The role of p53 in determining sensitivity to radiotherapy. Nature Reviews Cancer 3:117-129.
[5] A.V. Gudkov and E.A. Komarova, op. cit.

clinical and clinical settings by various groups. Indeed, human prostate cancer cell lines have been shown to become highly sensitive to ionizing radiation upon infection with an adenoviral vector containing the wild-type p53 in a viral dose-dependent manner, which also resulted in induction of G1 cell cycle arrest.[6] Growth of human cervical cancer cells have also been shown to be inhibited by a combination of ionizing radiation and p53 added by viral transduction at a rate that was significantly higher than when the cells were treated by either method alone.[7]

In a clinical study involving patients with advanced nasopharyngeal carcinoma (NPC), 42 subjects who were treated with a combination of adenoviral p53 gene therapy by intratumoral injection and local treatment with radiotherapy showed remarkable complete tumor response rate of 2.73 times higher than those 40 control patients who received radiotherapy alone.[8] In addition, locoregional recurrence observed in follow-ups over a period of 6 years in the combination treatment group was only 2.7% compared to 28% for the group that received radiotherapy alone.  Thus, at least for this study treatment of tumors in patients who received both gene therapy and radiation showed not only rapid complete tumor response but also long-term inhibition of local recurrence.

Solid tumors are complex structures involving heterogeneous types of tumor cells, stromal cells that support structure, endothelial cells that are involved in its vasculature, infiltrating immune cells of various kinds that are likely is suppressed state, and a subpopulation of cancer stem cells (CSCs). In particular, the CSCs have caught the attention of many investigators for they seem to be involved in resistance to genotoxic treatments, in the repopulation of the tumor mass, and in distant metastases (see review).[9]    Certain studies show that p53 is highly involved in the suppression of CSCs[10] [11] and that perhaps loss of p53 could lead to genetic instability, which in turn results in plasticity, a hallmark of CSCs, of certain phenotypes in the tumor population due to random mutations and clonal evolution.[12] Loss of p53 and deregulation of growth factor signalling pathways are thought be involved in the transformation of adult neural stem cells, and it is suggested treatments involving reactivation of p53 in brain tumor stem cell populations should be explored.[13]  In breast cancers, studies show that tumor cells can acquire stem cell properties when p53 functions are lost.[14] As the focus in cancer treatment is turning towards the control of CSCs in which p53 seems to be central in its regulation, it is perhaps time to reconsider the role of p53 gene therapy in combination with conventional treatments in the development of highly effective regimens for various types of solid tumors.

[6] R. Sasaki, T. Shirakawa, Z. Zhang, A. Tamekane, A. Matsumoto, K. Sugimura, M. Matsuo, S. Kamidono, and A. Gotoh (2009). Additional gene therapy with Ad5CMV-p53 enhanced the efficacy of radiotherapy in human prostate cancer cells. Intl J Radiation OncoBiologyPhysics 51:1336-1345.
[7] J.J. Huh, J.K. Wolf, D.L. Fightmaster, R. Leutan, and M. Follen (2003). Transduction of adenovirus-mediated wild-type p53 after radiotherapy in human cervical cancer cells. Gynecologic Oncology 89:243-250.
[8] J.J. Pan, S.W. Zhang, C.B. Chen, S.W. Xiao, Y. Sun, C.Q Liu, X. Su, D.M. Li, G. Xu, B. Xu, and Y.Y. Lu (2009). Effect of recombinant adenovirus-p53 combined with radiotherapy on long-term prognosis of advanced nasopharyngeal carcinoma. J Clin Oncol 27:799-804.
[9] C.T. Jordan, M.L. Guzman, and M. Noble (2006). Cancer stem cells. N Eng J Med 355:1253-61.
[10] M. Zhang, F. Behbod, R.L. Atkinson, M.D. Landis, F. Kittrell, D. Edwards, D. Medina, A. Tsimelzon, S. Hilsenbeck, J.E. Green, A.M. Michalowska, and J.M. Rosen (2008). Identification of tumor-initiating cells in a p53-null mouse model of breast cancer. Cancer Res 4674-82.
[11] S. Godar, T.A. Ince, G.W. Bell, D. Feldser, J.L. Donaher, J. Bergh, A. Liu, K. Miu, R.S. Watnick, F. Reinhardt, S.S. McAllister, T. Jacks, and R.A. Weinberg (2008). Growth-inhibitory and tumor-suppressive functions of p53 depend on its repression of CD44 expression. Cell 134:62-73.
[12] D.J. Jerry, L. Tao, H. Yan (2008). Regulation of cancer stem cells by p53. Breast Cancer Res 10:304
[13] S-M Hede, I. Nazarenko, M. Nister, M.S. Lindstrom (2010). Novel perspectives on p53 function in neural stem cells and brain tumors. J Oncol 2011:1-11.
[14] H. Mizuno, B.T. Spike, G.M. Wahl, and A.J. Levine (2010). PNAS USA 107:22745-22750.