ISSN 00062979, Biochemistry (Moscow), 2014, Vol. 79, No. 5, pp. 385390. © Pleiades Publishing, Ltd., 2014. Original Russian Text © A. V. Lichtenstein, 2014, published in Biokhimiya, 2014, Vol. 79, No. 5, pp. 493500.
REVIEW
Cancer Research: A Hurdle Race A. V. Lichtenstein Blokhin Cancer Research Center, Institute of Carcinogenesis, Kashirskoe Shosse 24, 115478 Moscow, Russia; fax: (499) 3241205; Email:
[email protected] Received January 9, 2014 Revision received January 24, 2014 Abstract—Cancer research has shifted in recent years from studying intracellular processes (identification of damaged genes and signaling pathways) to extracellular (hierarchy of tumor cells, cell transitions, clone competition) and tissue (interac tions of a tumor with its environment) research. But then the next step seems to be logical: studying biochemistry of tumor bearing organisms (namely, cancerinduced changes in cellular and tissue metabolism leading to the organism’s death). These data can help to develop new methods of cancer treatment. This article discusses some of the challenges of contem porary oncology and possible ways to overcome them. DOI: 10.1134/S0006297914050010 Key words: secretome, cancer therapy, tumorbearing organism, interception therapy
A generally accepted opinion is that only a complete and selective destruction of tumor cells can provide victo ry over cancer [1, 2]. This conviction guides basic research searching for characteristic properties of a can cer cell, the hallmarks of cancer [3], so as to find among them the “Achilles heel”, the goal of target therapy. This approach does not provide much reason for optimism [4]. Given the enormous complexity of living cells in general and the extraordinary “ingenuity” of can cer cells in particular, it is difficult to predict how long it will take to come up with a full description of a cancer cell. In addition, it is not clear a priori whether cancer cells possess such a vulnerability that could provide their radical and selective (not affecting normal cells) destruc tion. The fact that even histologically similar tumors dif fer significantly makes the possibility of the existence of a universal cure for cancer highly unlikely. Obvious difficulties in the direct solution of the problem (radical and selective tumor eradication) encourage the search for alternative approaches (descrip tion of some of them can be found in a recent review by Gerashchenko et al. [5]). Leaders of the United States National Cancer Institute have recently supported the Provocative Questions Initiative, which also reflects the insistent urge for nontrivial ideas [6].
DORMANT CANCER Dormant tumors (cancer in situ) – small, micro scopically clearly malignant tumors with no clinical man
ifestation – provide lots of food for thought on how to tame cancer. These kinds of lesions are detected at autop sy of people who died from injuries or nononcological diseases. The authors of the essay “Cancer without Disease” dedicated to this phenomenon consider it to be a regularity rather than an accidental discovery as it was thought until recently [7]. For example, in situ breast can cer is discovered in more than a third of women aged 40 50 years with no history of cancer in their lives (progres sive malignant tumor is diagnosed in only 1% of women in this age group). Similar figures characterize prostate pathology in men. Virtually all people aged 5070 years show in situ thyroid gland cancer, while only 0.1% of this age group is diagnosed with malignant cancer of this localization. If we take into account the fact that highly effective diagnostic tools (Xray, MRI, CT, PET, etc.) are hardly ever used in autopsy, which is usually limited to rather superficial examination, we can assume that the frequency of in situ cancer is very high (presumably also in other, not only the abovelisted localizations) [8]. Thus, we can conclude that initial pathological changes are quite common in elderly people, and that they start pro gressing and changing into lethal tumors only in a rela tively small portion of this group. Stating the possibility in principle of “peaceful coex istence” of an organism and a tumor brings forth two problems, fundamental and clinical. The first includes the need to identify, first, the molecular mechanisms that make this “peaceful coexistence” possible, and second, the stimuli that can “awaken” the dormant center. This essential problem is far from being solved. We can assume
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that the organism’s immune status as well as favorable balance of pro and antiangiogenic factors play impor tant roles in maintaining the balance [79]. It is the latter factor that can explain the low rate of solid tumors in patients with Down’s syndrome: endostatin level (angio genesis inhibitor) is increased in their blood due to an additional copy of chromosome 21. However, undoubted ly there are also other yet poorly understood factors involved in the development of the phenomenon of in situ cancer. A tumor is not an autonomous entity – its develop ment is determined by its interaction with its microenvi ronment (stromal cells, immune system, endothelium). Mutual influences are mediated by secreted molecules (cytokines, chemokines, growth factors) and extracellular vesicles (exosomes, ectosomes, apoptotic bodies). Exosomes, figuratively compared to “messages in a bot tle”, form another system of intercellular cooperation along with the endocrine and nervous systems [1113]. They contain information (proteins, mRNA, miRNA) with educational and instructional functions (i.e. it affects the phenotype of cell partners by providing them with new functions). Informational flows are directed both ways, which allows the microenvironment to play an active role in tumor development. For example, inactiva tion of the TGFβ type 2 receptor gene in mouse fibro blasts and consequent increase in paracrine stimulation lead to the transformation of normal prostate and stom ach epithelium [14], and carcinomaassociated fibro blasts can transform cultured BPH1 cells normally non tumorigenic in nude mice to become tumorigenic [15]. Thus, the role of tissue homeostasis appears to be very important in carcinogenesis; its disturbances can even be responsible for initiation of cell transformation, while gene mutations in epithelial (future cancer) cells might be secondary events [8]. “Responsibility” for tumor development is likely to be not individual, but col lective (apparently it is incorrect to put this responsibility solely on that single cell with random oncogenic muta tions; it is the entire organism that is likely to be “guilty” due to its congenital and/or acquired predispositions to oncogenesis). From this perspective, “dormant” cancer can be viewed as a temporary inability of the tissue envi ronment to actively support small foci of malignant growth; it is also important to keep in mind that this tem porary condition can continue for an indefinitely long time [16]. Mechanisms responsible for the maintenance of this state still need to be discovered; they can become the point of application of fundamentally new prevention methods [7]. The second (directly clinical) problem created by the phenomenon of dormant cancer concerns the choice of medical tactics when detecting a small tumor in a rela tively healthy organism. A common strategy of early diag nostics is focused on identifying such minimal (preferably still asymptomatic) loci of pathological changes for their
subsequent radical removal. Today, such a discovery caus es immediate actions (biopsy, radiation, surgery, chemotherapy). However, the data discussed above sug gest a more rational cautious tactic embracing evaluation of the general clinical status of the patient, activity, and dynamics of the process prior to any active treatment [5]. Wrong choice of tactics is fraught with the risk to awaken the dormant “hornet’s nest” with all the ensuing conse quences (often without having effective means to treat them). For example, any interference inevitably causes inflammation, which stimulates the malignant process [17], and chemotherapy has many side effects, con tributes to the development of drugresistant clones and, furthermore, can sometimes even stimulate tumor growth [18, 19].
WHY IS TARGETED THERAPY INEFFECTIVE? A fundamental problem, the huge variety of malig nant tumors, has been formulated in an article dedicated to this key issue of modern oncology [20]. We have in mind the differences between individual tumors as well as between the clones within each of them [5, 21]. Sequencing the genomes of normal and cancer cells has revealed the development of this variety in the course of Darwinian evolution [2]. Thus, the mechanism of the phenomenon that had been long known to clinicians on an intuitive level was clarified. First, it became apparent that cell transformation can follow many different paths (tumor phenotype can be determined by different genotypes). About 140 genes belonging to 12 signaling pathways whose driver muta tions can cause cell transformation have been identified [2]. As 28 driver mutations (of many possible) are usual ly enough to cause tumor development, there is obvious ly an abundance of options for achieving the same result (phenotypes of thus formed tumors bear the imprint of the primary genetic defects). Second, the cancer cell genome is characterized by inherent instability; as a result, socalled passenger muta tions are accumulated in these cells. Until recently pas senger mutations have been considered neutral (i.e. not related to carcinogenesis); however, they seem to play an important role. For example, it seems unreasonable to classify the mutations in noncoding (not involved in pro tein synthesis) genome as meaningless “passengers”, as these sequences were found to possess diverse regulatory functions [22]. This fact as well as the recently discovered paradoxical phenomenon of mutual influence of func tionally unrelated genes united by the common network of miRNA–mRNA interactions [23] suggest that a vary ing and unstable mutation background consisting of thousands of “passengers” contributes significantly to the uniqueness of each tumor. Computer simulation confirms that collective “burden” of multiple mutations (even BIOCHEMISTRY (Moscow) Vol. 79 No. 5 2014
TUMOR–ORGANISM INTERACTIONS “weak” individually) significantly affects tumor progres sion [24]. Third, carcinogenesis is known to be comprised of two constituents: genetic defects (changes in the DNA structure) and epigenetic shifts (aberrant realization of genetic information manifested in abnormal DNA methylation, histone modifications, miRNA synthesis, etc.) [2529]. Epigenetic regulation allows “reading” the same genome differently and translating it into different phenotypes, a process taking place both in the course of embryonic development and in carcinogenesis. This extremely complex and not fully understood system is quite labile and prone to random fluctuations; it responds to stress and cellular microenvironment [28, 3032]. It is apparently the activity of this system that causes different drug resistance in genetically identical cells [33]. And fourth, clones within a tumor apparently undergo mainly not “linear”, but “branched” evolution [21, 34, 35]. The early theory suggested the replacement of less fit clones for the most “advanced” ones resulting in relative tumor homogeneity at the successive stages of its development [36]. Orderly accumulation of specific mutations in a series of colon changes (polyp → adenoma → cancer) with con stant domination of a single clone also supported the con cept of “linear” evolution [37]. However, using genome wide massive parallel sequencing and exome (i.e. the sum of exons) sequencing of individual cells made it obvious that the events taking place inside a tumor may develop dif ferently from the way they were originally seen. Recent studies support this understanding [34]. Thirty biopsy sam ples were obtained from four kidney cancer tumors and their metastases to determine exome mutations, chromoso mal aberrations, and ploidy in them. The degree of intratu moral heterogeneity exceeded the worst expectations: a) twothirds of the mutations were not universal (found only in individual biopsy samples); b) different parts of the same tumor had diametrically opposite prognostic indicators; c) inactivating mutations in tumor suppressor genes SETD2, PTEN, KDM5C were discovered to be different in different sections of the same tumor, indicating convergent pheno typic evolution (in other words, different cells acquire these mutations independently); d) the majority (26 of 30) of biopsy samples had different allelic imbalance; e) intratu moral heterogeneity was shown to evolve in the course of disease development [34]. A similar study of 23 brain tumors showed that mutation profiles of primary gliomas and their recurrences occurring after the removal of the pri mary lesion differ significantly in many cases. For example, driver mutations of TP53, ATRX, SMARCA4, and BRAF were present in primary tumors and were absent from their recurrences. This observation indicates the appearance of many recurrences from cells being at the very early stages of “cancer” evolution [19]. Thus, the tumor appears to be “a tree with a branched crown” [5] or even in some cases “a tree with cloven trunk and crowns”, which explains its vitality. The BIOCHEMISTRY (Moscow) Vol. 79 No. 5 2014
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crown branches are genetically and epigenetically similar, but not identical. Removal of any single branch (even the strongest one) through targeted therapy can slow down the tumor growth, but it will not stop it (the neighboring branches, being resistant to a particular drug, will ulti mately fill the breach). These data, among other things, also question the very possibility of individualized cancer therapy, which is based on determining the molecular “profile” of a partic ular tumor. The problem is that biopsy samples, as shown above, are not sufficiently representative, and compre hensive research of the entire tumor mass is hardly possi ble technically. In addition, different tumor clones may send opposite diagnostic and prognostic “signals”. Branching evolution and clonal diversity of malig nant tumors cause some researchers to doubt even the very possibility of effective cancer therapy [38].
TUMOR AS ECOSYSTEM One of the projects that received significant funding (over two million USD) within the abovementioned pro gram “Provocative Questions Initiative” is based on the idea of “adaptive” therapy [20]1. The authors call for “respecting the laws of evolution”: not to ignore them, but try to use them for the benefit of the course. The tumor is seen as a complex ecological system [39] where individual cell groups have very different microenvironment. The latter not only exerts a strong selective pressure (primarily via such factors as hypoxia, acidosis, and reactive oxygen species), but also promotes genetic instability, which almost inevitably leads to the development of clones with different types of drug resist ance. In case of an intact (i.e. not yet subjected to thera peutic treatment) tumor, resistant clones are marginal and their size is much smaller than that of dominant clones; smaller competitiveness is the price paid for evo lutionary acquisition of resistance. Both experimental data [33] and everyday clinical experience provide evi dence in favor of the original “marginality” of resistant clones: the first chemotherapy cycles usually lead to com plete visual disappearance of the tumor indicating the sensitivity of initially dominant clones. However, such a “successful” therapy leads to the previously marginal clones becoming dominant: released from the pressure of stronger competitors, resistant cells initiate the disease relapse. Thus, the treatment becomes the factor of the selection of resistant tumor cells [21]. The list of possible negative effects of chemotherapy does not end there. For example, in the case of surgical
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Three years earlier, a similar grant application filed by the same authors was rejected with “the worst ever received” reviews [6].
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removal of the primary tumor in patients with glioma and their subsequent treatment with the alkylating agent temozolomide (TMZ), over half of relapses apparently have iatrogenic (i.e. resulting from medical treatment) origin: their genome reveals characteristic signs of TMZ induced mutagenesis [19]. And finally, besides the wellknown general side effects (influencing the cells of digestive and hematopoi etic systems), chemotherapy may adversely affect the cells of the tumor microenvironment. Experiments on immunodeficient mice have shown that certain drugs (5 fluorouracil, oxyplatin, leucovorin) can paradoxically stimulate the growth of colon cancer by inducing tumor associated fibroblasts to secrete specific cytokines and chemokines, including interleukin17A [18]. Adaptive therapy is based on the choice of the “less er of two evils”, i.e. it makes no attempts of complete tumor destruction, instead it tries to keep the tumor with in “acceptable limits” (dominant, therapysensitive clones become the deterrent factor) [20, 39]. Coexistence of both clone types in the tumor, treatmentsensitive and resistant, permits to control the entire system by main taining the balance between them. Sublethal for cancer cells drug doses, continuous monitoring of tumor growth, and constant treatment cor rection aimed at maintenance of required balance are the means of adaptive therapy. This strategy has been success ful in experimental conditions (doubled lifespan in mice with malignant ovarian cancer) and will be tested in the near future in a small clinical study of patients with prostate cancer.
tems) [44, 45]. While local manifestations respond to sur gery and/or radiation relatively well, generalized tumor effects on the organism are elusive, they have hardly been studied, even though it is them that usually kill cancer patients (dissemination of cancer cells makes their physi cal elimination impossible, and patient’s death – inevitable). There is evidence indicating that cancer is a conser vative biological phenomenon, the programmed death of an organism [40, 4649]. But whatever the evolutionary origin of cancer is, the tumor objectively looks like a spe cial organ (referring to the development of a new tissue structure with a new function) [50], acting as a self destruct mechanism, which starts functioning when the “mutation burden” of an organism (the number of somatic mutations) exceeds a certain threshold. In all likelihood, it is the cancer cell “interactome”2 that is its deadly weapon. It includes “secretome”3 [5154], extra cellular vesicles [10, 12, 5559], extracellular DNA [60], and neurogenic factors [61]. Cancer cells use their inter actome/secretome to form their “niche” [62], provide their own blood supply [63], energy supply (at the expense of muscle mass) [64] and innervation [65], sub ordinate microenvironment, recruit normal cells, form premetastatic niche [66, 67], metastasize, and eventually kill their host. It can be assumed that while having the same possibilities as normal cells (both share the same genome), cancer cells realize their interactome according to their destructive program. The fact that normal cells actively participate in killing the organism indicates that signals coming from the tumor totally reprogram the nor mal development of a multicellular organism.
WHAT CAUSES DEATH OF CANCER PATIENTS? INTERCEPTION STRATEGY Ironically perhaps, the most important and unique feature of cancer cells, their ability to kill the organism (killer function) [40, 41], is not in the classic list of the key properties of a cancer cell (hallmarks of cancer) [3]. All the other properties (including the ability to metasta size) seem to be only additional means to support this key one, not to mention the fact that the majority of those hallmarks are not exclusive for cancer cells [42]. This omission is probably due to the predominant “in vitro centric” approach to cancer cell properties. However, who would be interested in cancer cells if they did not have a killer function? There hardly exists a more impor tant goal in experimental oncology than understanding its mechanism. At the same time, the very fact of the absence of this property in all the versions of “hallmarks of can cer” [3, 43] clearly demonstrates its complete disregard. From the “in vivocentric” perspective, cancer man ifests itself in two types of symptoms: local (bleeding, brain compression, obturation and/or perforation of res piratory or digestive tract) and generalized, systemic (many paraneoplastic syndromes affecting all body sys
In their recent paper, Vogelstein et al. mapped a strategy for fighting malignant tumors by a combination of “plan A” (prevention and early diagnostics) and “plan B” (anticancer therapy) [2]. This strategy can probably be supplemented by “plan C” (adaptive therapy) [20] and perhaps “plan D” (interception therapy aimed not at elimination of cancer cells, which is hardly reachable in practice, but at blocking the tumor/organism interac tome) [40, 41]. There are examples of successful application of this strategy in model systems: a) antibodies to interleukin23 enhance the immune response and prevent chemical car cinogenesis [68]; b) antibodies to VEGFR1 and VEGFR2 suppress the development of metastases in mice with VEGFR1and VEGFR2positive bone marrow cells involved in the formation of premetastatic niche [66, 67];
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All types of tumor–organism interactions. All the factors secreted by the cell. BIOCHEMISTRY (Moscow) Vol. 79 No. 5 2014
TUMOR–ORGANISM INTERACTIONS c) antibodies to MIC1 prevent cachexia in mice with prostate cancer xenografts [69]; d) in accordance with the data on predominant propagation of metastases in an acidic environment generated by the tumor, and data on tumor cell migration along a pH gradient, oral adminis tration to mice of sodium bicarbonate solution proved to be sufficient for neutralization of the intratumoral medi um, suppression of tumor growth and local invasion [70]; e) surgical or chemical sympathectomy of mice with prostate cancer blocked the development of this tumor at an early stage, and pharmacological blockade of cholin ergic receptors blocked its metastases, which led to signif icant increase in the animals’ lifespan [65] (in this regard, it seems interesting to mention epidemiological findings that mortality from prostate cancer decreased in patients taking βblockers [71]). The fundamental flaw of current cancer chemother apy is the phenomenon of “friendly fire”4 and the result ing side effects. One can hope that “interception” thera py based on another, unrelated to cytotoxicity principle, will not have this flaw. To implement this strategy in practice, we need to understand the mechanism of the killer function, i.e. we need not only to know what is happening in cancer cells (the goal of the main efforts today), but also to under stand the processes induced by cancer cells in the tumor bearing organism (today this area is terra incognita of fun damental oncology). Cancer studies have been evolving in recent years from intracellular signaling pathways to extracellular events: tumor interaction with its microen vironment. Now the next logical step seems to be neces sary: using the possibilities of highthroughput technolo gies (proteomics, genomics, epigenomics, metabolomics) to start systematic studies of the processes in organs and tissues affected by a tumor. Here the comparison of “tran scriptomes”, “proteomes”, and “metabolomes” from dif ferent tissues of intact and tumorbearing animals seems to be of particular interest. Then we could obtain a detailed understanding of the shifts taking place in a sick organism: what is wrong in a particular tissue at the molecular level and what factors are responsible for it. Recent discoveries emphasize the need to shift the focus of work from studying “cancer” (i.e. the tumor and its immediate environment) to researching the “oncolog ical process” understood as tumor–organism interaction in a single ecological system. Such an approach can pro vide answers to key questions: a) whether tumorinduced fatal processes are limited in number and specific; b) what factors of the tumor/organism interactome play the most important role; c) what metabolic steps and in what tis sues are critical in the implementation of a suicidal pro gram; d) what are the possibilities of cancellation of
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“Friendly fire” is an American military term for accidental shooting toward their own troops. BIOCHEMISTRY (Moscow) Vol. 79 No. 5 2014
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“phenoptosis”. Answers to these questions may help to create fundamentally new drugs free from the defects of traditional cytotoxic medications. Moreover, interception strategy may help to achieve the most longawaited goal, the radical elimination of the malignant tumor, due to its micro and macroenvironment ceasing to “support” the tumor.
REFERENCES 1. Hanahan, D., and Coussens, L. M. (2012) Cancer Cell, 21, 309322. 2. Vogelstein, B., Papadopoulos, N., Velculescu, V. E., Zhou, S., Diaz, L. A., and Kinzler, K. W. (2013) Science, 339, 15461558. 3. Hanahan, D., and Weinberg, R. A. (2011) Cell, 144, 646 674. 4. Leaf, C. (2004) Fortune, 149, 7688. 5. Gerashchenko, T. S., Denisov, E. V., Litviakov, N. V., Zavyalova, M. V., Vtorushin, S. V., Tsyganov, M. M., Perelmuter, V. M., and Cherdyntseva, N. V. (2013) Biochemistry (Moscow), 78, 12011215. 6. Varmus, H., and Harlow, E. (2012) Nature, 481, 436437. 7. Folkman, J., and Kalluri, R. (2004) Nature, 427, 787. 8. Hlatky, L., and Hahnfeldt, P. (2014) Cancer Res., 74, 659 664. 9. Ghajar, C. M. (2013) Sci. Transl. Med., 5, 188ec94. 10. Kharaziha, P., Ceder, S., Li, Q., and Panaretakis, T. (2012) Biochim. Biophys. Acta, 1826, 103111. 11. AlNedawi, K., Meehan, B., Micallef, J., Lhotak, V., May, L., Guha, A., and Rak, J. (2008) Nat. Cell Biol., 10, 619624. 12. Rak, J. (2013) Front. Pharmacol., 4, 114. 13. Roberts, C. T., and Kurre, P. (2013) Cancer Res., 73, 3200 3205. 14. Bhowmick, N. A., Chytil, A., Plieth, D., Gorska, A. E., Dumont, N., Shappell, S., Washington, M. K., Neilson, E. G., and Moses, H. L. (2004) Science, 303, 848851. 15. Hayward, S. W., Wang, Y., Cao, M., Hom, Y. K., Zhang, B., Grossfeld, G. D., Sudilovsky, D., and Cunha, G. R. (2001) Cancer Res., 61, 81358142. 16. Enderling, H., Anderson, A. R. A., Chaplain, M. A. J., Beheshti, A., Hlatky, L., and Hahnfeldt, P. (2009) Cancer Res., 69, 88148821. 17. Atsumi, T., Singh, R., Sabharwal, L., Bando, H., Meng, J., Arima, Y., Yamada, M., Harada, M., Jiang, J. J., Kamimura, D., Ogura, H., Hirano, T., and Murakami, M. (2013) Cancer Res., 74, 814. 18. Lotti, F., Jarrar, A. M., Pai, R. K., Hitomi, M., Lathia, J., Mace, A., Gantt, G. A., Jr., Sukhdeo, K., Devecchio, J., Vasanji, A., Leahy, P., Hjelmeland, A. B., Kalady, M. F., and Rich, J. N. (2013) J. Exp. Med., 210, 28512872. 19. Johnson, B. E., Mazor, T., Hong, C., Barnes, M., Aihara, K., McLean, C. Y., Fouse, S. D., Yamamoto, S., Ueda, H., Tatsuno, K., Asthana, S., Jalbert, L. E., Nelson, S. J., Bollen, A. W., Gustafson, W. C., Charron, E., Weiss, W. A., Smirnov, I. V., Song, J. S., Olshen, A. B., Cha, S., Zhao, Y., Moore, R. A., Mungall, A. J., Jones, S. J. M., Hirst, M., Marra, M. A., Saito, N., Aburatani, H., Mukasa, A., Berger, M. S., Chang, S. M., Taylor, B. S., and Costello, J. F. (2014) Science, 343, 189193.
390
LICHTENSTEIN
20. Gillies, R. J., Verduzco, D., and Gatenby, R. A. (2012) Nat. Rev. Cancer, 12, 487493. 21. Fisher, R., Pusztai, L., and Swanton, C. (2013) Br. J. Cancer, 108, 479485. 22. Pennisi, E. (2013) Science, 340, 910910. 23. Salmena, L., Poliseno, L., Tay, Y., Kats, L., and Pandolfi, P. P. (2011) Cell, 146, 353358. 24. McFarland, C. D., Korolev, K. S., Kryukov, G. V., Sunyaev, S. R., and Mirny, L. A. (2013) Proc. Natl. Acad. Sci. USA, 110, 29102915. 25. Lotem, J., and Sachs, L. (2002) Semin. Cancer Biol., 12, 339346. 26. Baylin, S. B., and Ohm, J. E. (2006) Nat. Rev. Cancer, 6, 107116. 27. EsquelaKerscher, A., and Slack, F. J. (2006) Nat. Rev. Cancer, 6, 259269. 28. Feinberg, A. P. (2007) Nature, 447, 433440. 29. Mayr, C., and Bartel, D. P. (2009) Cell, 138, 673684. 30. Esteller, M. (2006) Br. J. Cancer, 94, 179183. 31. Esteller, M. (2007) Nat. Rev. Genet., 8, 286298. 32. Ting, A. H., McGarvey, K. M., and Baylin, S. B. (2006) Genes Dev., 20, 32153231. 33. Kreso, A., O’Brien, C. A., van Galen, P., Gan, O. I., Notta, F., Brown, A. M., Ng, K., Ma, J., Wienholds, E., Dunant, C., Pollett, A., Gallinger, S., McPherson, J., Mullighan, C. G., Shibata, D., and Dick, J. E. (2013) Science, 339, 543548. 34. Gerlinger, M., Rowan, A. J., Horswell, S., Larkin, J., Endesfelder, D., Gronroos, E., Martinez, P., Matthews, N., Stewart, A., Tarpey, P., Varela, I., Phillimore, B., Begum, S., McDonald, N. Q., Butler, A., Jones, D., Raine, K., Latimer, C., Santos, C. R., Nohadani, M., Eklund, A. C., SpencerDene, B., Clark, G., Pickering, L., Stamp, G., Gore, M., Szallasi, Z., Downward, J., Futreal, P. A., and Swanton, C. (2012) N. Engl. J. Med., 366, 883892. 35. Swanton, C. (2012) Cancer Res., 72, 48754882. 36. Nowell, P. C. (1976) Science, 194, 2328. 37. Fearon, E. R., and Vogelstein, B. (1990) Cell, 61, 759767. 38. Kaiser, J. (2013) Science, 339, 15431545. 39. Aktipis, C. A., Boddy, A. M., Gatenby, R. A., Brown, J. S., and Maley, C. C. (2013) Nat. Rev. Cancer, 13, 883892. 40. Lichtenstein, A. V. (2008) Med. Hypotheses, 71, 839850. 41. Lichtenstein, A. V. (2010) Clin. Epigenetics, 1, 85100. 42. Lazebnik, Y. (2010) Nat. Rev. Cancer, 10, 232233. 43. Hanahan, D., and Weinberg, R. A. (2000) Cell, 100, 5770. 44. Tisdale, M. J. (2002) Nat. Rev. Cancer, 2, 862871. 45. Finora, K. (2003) Clin. Tech. Small Anim. Pract., 18, 123 126. 46. Graham, J. (1992) in Cancer Selection: The New Theory of Evolution, Aculeus Press, Lexington, USA. 47. Sommer, S. S. (1994) Hum. Mutat., 3, 166169. 48. Manskikh, V. N. (2004) Essays on Evolutionary Oncology (Perelmuter, V. M., ed.) [in Russian], SSMU Publisher, Tomsk. 49. Lichtenstein, A. V. (2005) Cancer Cell Int., 5, 5. 50. Bissell, M. J., and Radisky, D. (2001) Nature Rev. Cancer, 1, 4654. 51. Balkwill, F. (2004) Nat. Rev. Cancer, 4, 540550. 52. Kulbe, H., Levinson, N. R., Balkwill, F., and Wilson, J. L. (2004) Int. J. Dev. Biol., 48, 489496.
53. Kulbe, H., Thompson, R., Wilson, J. L., Robinson, S., Hagemann, T., Fatah, R., Gould, D., Ayhan, A., and Balkwill, F. (2007) Cancer Res., 67, 585592. 54. Wels, J., Kaplan, R. N., Rafii, S., and Lyden, D. (2008) Genes Dev., 22, 559574. 55. Coppe, J. P., Patil, C. K., Rodier, F., Sun, Y., Munoz, D. P., Goldstein, J., Nelson, P. S., Desprez, P. Y., and Campisi, J. (2008) PLoS Biol., 6, 28532868. 56. Khwaja, F. W., Svoboda, P., Reed, M., Pohl, J., Pyrzynska, B., and van Meir, E. G. (2006) Oncogene, 25, 76507661. 57. Kim, S., Takahashi, H., Lin, W. W., Descargues, P., Grivennikov, S., Kim, Y., Luo, J. L., and Karin, M. (2009) Nature, 457, 102106. 58. Nikitina, I. G., Sabirova, E. Yu., Karpov, V. L., Lisitsyn, N. A., and Beresten’, S. F. (2013) Mol. Biol. (Moscow), 47, 668673. 59. Gusachenko, O. N., Zenkova, M. A., and Vlassov, V. V. (2013) Biochemistry (Moscow), 78, 17. 60. Wen, F., Shen, A., Choi, A., Gerner, E. W., and Shi, J. (2013) Cancer Res., 73, 42564266. 61. Ayala, G. E., Dai, H., Powell, M., Li, R., Ding, Y., Wheeler, T. M., Shine, D., Kadmon, D., Thompson, T., Miles, B. J., Ittmann, M. M., and Rowley, D. (2008) Clin. Cancer Res., 14, 75937603. 62. BarcellosHoff, M. H., Lyden, D., and Wang, T. C. (2013) Nat. Rev. Cancer, 13, 511518. 63. Bergers, G., and Benjamin, L. E. (2003) Nat. Rev. Cancer, 3, 401410. 64. Luo, Y., Yoneda, J., Ohmori, H., Sasaki, T., Shimbo, K., Eto, S., Kato, Y., Miyano, H., Kobayashi, T., Sasahira, T., Chihara, Y., and Kuniyasu, H. (2014) Cancer Res., 74, 330 340. 65. Magnon, C., Hall, S. J., Lin, J., Xue, X., Gerber, L., Freedland, S. J., and Frenette, P. S. (2013) Science, 341, 1236361. 66. Kaplan, R. N., Riba, R. D., Zacharoulis, S., Bramley, A. H., Vincent, L., Costa, C., MacDonald, D. D., Jin, D. K., Shido, K., Kerns, S. A., Zhu, Z., Hicklin, D., Wu, Y., Port, J. L., Altorki, N., Port, E. R., Ruggero, D., Shmelkov, S. V., Jensen, K. K., Rafii, S., and Lyden, D. (2005) Nature, 438, 820827. 67. Kaplan, R. N., Rafii, S., and Lyden, D. (2006) Cancer Res., 66, 1108911093. 68. Langowski, J. L., Zhang, X., Wu, L., Mattson, J. D., Chen, T., Smith, K., Basham, B., McClanahan, T., Kastelein, R. A., and Oft, M. (2006) Nature, 442, 461465. 69. Johnen, H., Lin, S., Kuffner, T., Brown, D. A., Tsai, V. W. W., Bauskin, A. R., Wu, L., Pankhurst, G., Jiang, L., Junankar, S., Hunter, M., Fairlie, W. D., Lee, N. J., Enriquez, R. F., Baldock, P. A., Corey, E., Apple, F. S., Murakami, M. M., Lin, E. J., Wang, C., During, M. J., Sainsbury, A., Herzog, H., and Breit, S. N. (2007) Nat. Med., 13, 13331340. 70. Estrella, V., Chen, T., Lloyd, M., Wojtkowiak, J., Cornnell, H. H., IbrahimHashim, A., Bailey, K., Balagurunathan, Y., Rothberg, J. M., Sloane, B. F., Johnson, J., Gatenby, R. A., and Gillies, R. J. (2013) Cancer Res., 73, 15241535. 71. Grytli, H. H., Fagerland, M. W., Fossa, S. D., Tasken, K. A., and Haheim, L. L. (2013) Prostate, 73, 250260.
BIOCHEMISTRY (Moscow) Vol. 79 No. 5 2014
