The ability of cancer to affect various species of animals is a paradoxical fact. The matter is that carcinogenesis is closely related to cellular proliferation: due to cell divisions, accumulation of mutations in the cellular genome is possible (see below). Though the μ value (mutation rate per gene and cell division) varies greatly (Vijg 2000), its existence and non-zero values are evidence of this intimate link. Proliferation and transformation are thus conjugate processes: if proliferation is sufficiently intensive, the appearance of a completely transformed (i.e. cancer) cell is a matter of time.

This logic suggests that the probability of cancer increases with the mass of the animal (as the number of proliferating cells and the probability of mutations in them are higher) and its life span. It may be assumed, therefore, that if the resistances of animal cells to malignant transformation were the same, blue whales (weighing more than 100 tons) would all be suffering from cancer and disappearing as a species, whereas mice (weighting about 20 g) would not have cancer at all. In fact, however, nothing of this kind takes place: all species (whales, mice, and man) are susceptible to cancer but neither becomes extinct.

Explaining this so-called Peto paradox (Peto et al. 1975) is possible by assuming an inequality of transformation resistance of cells of various species (in whales it should be much higher than in mice). One of the most important determinants of the transformation resistance is the number of stages of transformation: the greater this number, the more strongly the individual is protected against cancer (Frank 2004). Indeed, fibroblasts of man are much more difficult to transform than fibroblasts of mouse because of a greater number of mutations required for this purpose in the former (Hahn and Weinberg 2002). Thus, the Peto paradox (the more or less equal susceptibility to cancer of animals strikingly differing in mass and life span) is the evidence of species-specific adaptation of cell transformation resistance. If cancer had any unfavorable influence on viability of a species, then its ousting beyond the limits of the species’ life span by means of augmentation of the transformation resistance would be easily achieved. In one peculiar case of the naked mole rat, in which tumors have never been observed, this extraordinary resistance to cancer has come about due to a relatively slight modification of regulatory network, namely, the involvement of both p16(ink4a) and p27(Kip1) tumor suppressors in the control of contact cell inhibition (in human and mouse, as opposed to mole rat, contact inhibition is triggered only by the induction of p27) (Seluanov et al. 2009). The reason for the appearance of such a unique trait remains unknown, but this exception to the general rule shows that elimination of cancer, if necessary, would present no difficulty. The susceptibility to cancer of most animals, by the rule of contraries, is therefore the evidence of its evolutionary usefulness.

Malignant transformation affects different species and different tissues. The latter, too, differ in their mass and proliferation rate and, accordingly, in transformation resistance: in fact, for tumor appearance in different human tissues, different numbers of mutations are required (Renan 1993). This is because cell type-specific differences exist in the requirements for tumorigenic transformation (Rangarajan et al. 2004). The fact that transformation resistance of cells is not only species-specific but also cell type-specific indicates that genetic as well as epigenetic mechanisms participate in its formation.

The probability of appearance of a tumor in an individual is a function of intensity of mutagenesis, which in turn is determined by the balance of two opposite processes: mutagenesis and anti-mutagenesis. Mutagenic factors are subdivided, by their origin, into two types: exogenous and endogenous. Factors from the external environment are chemical carcinogens, ultraviolet irradiation, ionizing radiation, viral and bacterial infections. This “external” component of mutagenesis is subject to certain correction and is therefore an important object of preventive actions.

The “intrinsic” component of mutagenesis, that cannot be controlled at present, is caused by fundamental processes: cell division entails inevitable errors of replication; metabolic processes and respiration lead to accumulation of aggressive reactive oxygen species (ROS); telomere shortening during cell divisions results in chromosome aberrations; spontaneous DNA depurination and methylcytosine deamination bring about DNA damage; phagocytosis of apoptotic bodies is related to a wide-scale natural transfection.

Mutagenesis is opposed by mechanisms of DNA repair and apoptosis that are capable of strongly, by many orders of magnitude, reducing mutation rate but incapable of eliminating it completely. As a result, vital activity is accompanied by a parallel mutagenesis and, as its consequence, the organism is gradually “creeping up into carcinogenesis” (Lichtenstein 2009). The speed of this process, which determines the probability of appearance of a tumor in the individual, is, as a rule, low. Thanks to that, the majority of people throughout their life do not form tumors (according to a saying, “not everyone lives long enough to reach his/her cancer”). However, in about 20% of people, the balance of counteracting forces (external and internal mutagenesis, on the one hand, and protective mechanisms of DNA repair and apoptosis, on the other) develops unfavorably, the process of “creeping into carcinogenesis” is accelerated and, as a result, cancer overtakes the individual in, depending on the acceleration rate, elderly or even young age (in the latter case, hereditary genetic defects often play a key role).

Thus, the prevalent opinion on randomness of cancer, based, first, on a relative rarity of the disease (overall, two out of ten people suffer) and, second, on the fact that cancer is invoked by random events (mutations), requires apparently a certain revision. Cancer is most likely a natural, but not inevitable, phenomenon. The same can be said about old age: after all it is also natural but not inevitable (it is quite possible to die young).

A completely transformed cell arises after several rate-limiting events (mutations) affecting a number of key genes (oncogenes and suppressor genes). The number of such driver mutations responsible for driving the initiation, progression, or maintenance of the tumor varies, depending on cell origin, from 4 to 12–15 (Renan 1993; Wood et al. 2007). Mutations are rare events, and accumulation of such a large number in one cell is hardly probable. If it nonetheless occurs, this happens because with every cancer-promoting mutation the cell gets some selective advantage and forms a clone. What is improbable for a cell is quite probable for a clone, and the bigger the clone, the higher is the probability of the next mutation in one of the daughter cells. The process then repeats itself. Thus, according to the theory of multi-stage carcinogenesis, cell transformation is a Darwinian process of consecutive cycles of mutation–selection (Armitage and Doll 1954).

Accumulation of the mutant cells in a population is symbolized by “the mutational pyramid”, at which base are cells with the lowest number of cancer-promoting mutations, and at the top, with the greatest (Lichtenstein 2005b). As mutagenesis is progressing (and the mutational pyramid grows in width and height), the transformation resistance of the cell is depleted, thus serving as a countdown trigger. Its full depletion in the cell, which is at the top of the pyramid (i.e. completely transformed) marks the transition of carcinogenesis from the latent phase (in which the “underground” of the tumor, consisting of precancerous cells at different stages of transformation, is formed) to an open clinical phase (when tumor becomes evident) (Lichtenstein 2006).

An obligatory presence in each tumor of an “underground”, the assumption that follows from general reasoning, is supported by discovery of “field cancerization”, i.e. large and surrounding the tumor “patches” of partially transformed cells, recognized on the basis of mutations in TP53 but remaining undetectable by routine diagnostic techniques (Braakhuis et al. 2003). The impossibility of defining the borders of these fields and completely removing them during surgical operation is, apparently, the principal cause of tumor relapse.

Mutagenesis takes place in all cells of the body, and, hence, in each tissue a mutational pyramid grows. Their growth can be compared to sprinting on parallel lanes: all runners are running, but the winner (in this case, who first generates a tumor) is determined by casual circumstances. If the speed of the leader drops for some reason, its place is taken by another runner. This explains the so called “effect of communicating vessels” (as it was named by a Russian physician J.I. Lorie): a decrease in incidence of one form of cancer often does not result in a decrease in overall cancer incidence—the “niche” is filled with other forms (for instance, a drop in stomach cancer among the Japanese who moved to the US, is compensated by a rise in the incidence of lung cancer). Thus, one can conclude that tumor localization is random, but its appearance is natural (owing to the constantly going and progressing mutagenesis). The fact that not every individual faces an oncologic disease during life is explained, apparently, by a prevailing mortality from other causes.

The recently proposed concept of phenoptosis (programmed death of an organism) postulates an existence in biology of the so-called Samurai principle (“it is better to die than to be wrong”). The biological system is suggested to possess a built-in self-destruction program. This program is not active usually and comes into effect when the system begins to pose hazard to another one, which is standing above in the biological hierarchy (Longo et al. 2005; Skulachev 1999). The most fundamental manifestation of this altruistic principle is apoptosis, which eliminates a cell when it begins to be a threat for the multi-cellular community. At a signal from the outside, the cell makes a suicide for the sake of maintenance of the tissue homeostasis and renewal, or as a necessary condition of morphogenesis during embryonic development. The signal, which activates the self-destructive program, can arise also inside the cell (e.g. in the case of DNA damage).

If cancer is also a case of phenoptosis, a question arises, “Which advantages does it confer to the higher hierarchical system—to the species?” Apparently, these are the same that apoptosis confers to the multi-cellular community, namely, the negative selection of the hazardous individuals. Indeed, in hereditary cancer syndromes (when the “sanitary” role of cancer most evidently manifests itself), the tumors appear in reproductive age and are often multiple, what does not leave the individual any chance of survival. By this means, germ-line mutations of functionally important genes, which otherwise would have a high probability of spreading in the population (Lichtenstein 2005b, Lichtenstein 2008), are generally eliminated from the gene pool (Ponder 2001). A computational model of cancer progression suggests that an additional protection against cancer would lead to significantly increased genetic predisposition to disease in the population as a whole (Frank 2004).

The fact that cancer mainly affects individuals of old age (>95% of total incidence) is often considered as an argument that it is selectively neutral. Such an interpretation raises doubts. A functionally important program, which is active at the reproductive age, will most likely be also active at an old age (even if it becomes useless or even harmful), since evolutionary mechanisms that could correct a situation, are inefficient at that age (the theory of antagonistic pleiotropy) (Kirkwood and Austad 2000). Thus, the high cancer incidence at advanced age can be considered as a side effect of a program designed for elimination of young carriers of mutant genes (the number of such individuals is relatively low but they are potentially quite hazardous). Cancer-related genes belong to “essential genes” (classified as lethal by mouse knockout experiments), and their mutant forms are, probably, more detrimental to fitness than those in other genes (Thomas et al. 2003).

Another hypothesis calling into question the general assumption that cancer represents simply a breakdown in normal physiology, suggests that it carries out an important function of maintenance of optimal level of germ-line mutagenesis. A very low mutagenesis would not provide the variability necessary for evolution of species, while a very high mutagenesis is fraught with many unfavorable consequences, since for each advantageous mutation, there are many detrimental ones. In this case, cancer is a mechanism for negative selection, which limits the upper level of mutagenesis and ensures an optimal mutation rate (Sommer 1994).

And, finally, cancer perhaps fulfills the important function of quality control at times of fast evolutionary changes of the species, especially associated with a body mass or life span increase, i.e. when the genome is yet insufficiently adapted to the new conditions (such situation arises, for example, in selective breeding of large dogs, which have, as a result, an extremely high cancer incidence) (Graham 1992; Leroi et al. 2003).

There are no doubts that the tumor begins from one transformed cell: the monoclonal origin of a tumor is one of fundamental notions of oncology. In a model system, using a method for reconstructing cell lineage trees from genomic variability caused by somatic mutations, it was found that the tumor initiated from a single founder cell (Frumkin et al. 2008). Does it mean that this first cell is to blame for the disease and that the disease is a casual event? Or, in other words, that carcinogenesis is a cell-autonomous process? Most likely, the real situation is more complex.

An unexpected result of recent studies suggests that transformation of the epithelial cells, which give rise to a malignant tumor, is a secondary event, while the primary changes arise in the tumor environment (Maffini et al. 2004). A rat mammary tissue recombination model and the chemical carcinogen N-nitrosomethyl urea (NMU) were used to determine whether the primary target of the carcinogen is the epithelium, the stroma or both tissue compartments. Mammary epithelial cells were exposed in vitro either to the carcinogen or vehicle before being transplanted into the cleared fat pads of rats exposed to carcinogen or vehicle. Neoplastic transformation of these mammary epithelial cells was shown to occur only when the stroma was exposed in vivo to NMU, regardless of whether the epithelial cells were exposed to the carcinogen. Mammary epithelial cells exposed in vitro to the carcinogen formed phenotypically normal ducts when injected into a non-treated stroma. It is not known how universal is such a sequence of events, but is doubtless that a tumor and its environment participate in carcinogenesis as equal partners.

Throughout the long process of transformation, the cell resides in an environment of normal neighbors and is exposed to their influence, which could be pro- and anti-carcinogenic. Since Virchow’s time, the association of cancer with a chronic inflammation is well known: not only does it always accompany tumor growth, but also very often precedes it (Balkwill and Mantovani 2001; Coussens and Werb 2002). Inflammatory cells secrete cytokines and chemokines, which bind to receptors on cancer cells and enhance their proliferation, migration and invasion.

There is evidence that carcinoma-associated fibroblasts (CAFs), which phenotypically differ from normal fibroblasts, possess the ability to stimulate carcinogenesis (Bhowmick et al. 2004; Olumi et al. 1999). The loss of TGF-β responsiveness in fibroblasts resulted in intraepithelial neoplasia in mouse prostate and invasive squamous cell carcinoma of the forestomach (Bhowmick et al. 2004). A question that remains unanswered concerns the so-called interdependent coevolution of clonal populations of carcinoma cells and CAFs, or, in other words, whether simultaneous generation of two symbiotic malignancies is possible. There are opposite opinions: some authors have found genetic alterations in CAFs, whereas others consider such findings as artifacts and deny their real existence (Allinen et al. 2004; Campbell et al. 2009; Eng et al. 2009; Weinberg 2008). No matter what the answer would be, one thing is clear: there are significant distinctions between normal and cancer-associated fibroblasts, these distinctions are heritable and are caused by specific patterns of gene expression (Allinen et al. 2004).

Senescent cells can also induce their normal neighbors to carcinogenesis. The state of senescence arises from the genotoxic stress of cells or depletion of their proliferative potential. Senescent cells secrete myriad of factors associated with inflammation and malignancy and acting by a paracrine mechanism. Premalignant mammary epithelial cells exposed to senescent human fibroblasts in mice undergo full malignant transformation. Obviously, senescent cells contribute to age-related pathology, including cancer (Coppe et al. 2008; Parrinello et al. 2005).

And, finally, conditions can exist in the body that favor predominant survival of the mutant cells with the altered metabolism. For example, under low-glucose conditions, mutations in oncogene K-RAS allow colorectal cells to outgrow their neighboring healthy cells with wild-type K-RAS. The cells with mutant K-RAS exhibit enhanced glucose uptake and glycolysis due to increased GLUT1 (glucose transporter-1) expression (Yun et al. 2009).

The capabilities of the environment are not limited to procarcinogenic effects. Tumor environment also possesses an opposite ability, namely to reverse tumor phenotype (this could hardly be imagined if one takes into consideration the irreversibility of tumor-inducing mutations). Mintz and Illmensee (1975) found that a mouse embryonic blastocyst microenvironment suppressed the tumorigenic phenotype of teratocarcinoma cells, which could give rise to normal tissues. These experiments have refuted the established notion about irreversibility of tumor phenotype. Recent studies using various embryonic models confirmed the earlier data, and have shown, in particular, a possibility of reversion of the metastatic phenotype of aggressive melanoma cells. Nodal signaling was found to be especially important, the inhibition of which promotes the reversion of melanoma cells towards a melanocytic phenotype (Hendrix et al. 2007). Some signal pathways have been identified (in particular, the SIAH1, presenilin 1, TSAP6, and translationally controlled tumor protein, TCTP), whose activation in tumor cells can result in the negation of genetic defects and lead to tumor reversion. This process involves a reprogramming mechanism using epigenetic and probably genetic tools (Telerman and Amson 2009).

It can be concluded that both cell-autonomous events (genetic perturbations) and actions of environment may contribute to carcinogenesis. The former are random, while the latter are, most likely, non-random and depend on the genetic constitution of the organism, that is, on a multitude of factors, some of which may have no explicit relation to carcinogenesis (e.g. genetic predisposition to inflammatory reactions, senescence-associated secretory phenotype, etc.).

One can envision the internal organization of the cell and organism as complex hierarchy of densely interlaced molecular networks with an abundance of feedback loops. The tumor is so strongly integrated into these networks (Albini and Sporn 2007; Allinen et al. 2004; Balkwill 2004; Bissell and Radisky 2001; Gallagher et al. 2005; Hill et al. 2005), that it is impossible to “isolate” and consider it with no connections with its environment, exactly as in the case of any other tissue. Cooperation between tumor and its environment is well established, what allows to consider a tumor like a special “organ” (Bissell and Radisky 2001). Indeed, a tumor meets the formal definition of an organ as an anatomically discrete complex of tissues, integrated to perform specific functions and has the necessary attributes: stem cells (cancer stem cells [CSC]) (Reya et al. 2001), hierarchical structure often simulating a normal tissue constitution (Perez-Losada and Balmain 2003), cellular specialization (Axelrod et al. 2006), structural and functional unity with the microenvironment (Albini and Sporn 2007; Merlo et al. 2006), and, as has been noted above, a specific function – the organism death (Lichtenstein 2005a). Tumors produce both stimulators and inhibitors of angiogenesis in their microenvironment and exhibit a growth slowdown with a possible asymptotic approach to a final tumor size, or “set point”, what indicates that the tumor maintains a vestige of normal tissue mass control. Developing tumors and organs may share an awareness of total mass through the exertion of an increasingly inhibitory influence on their own growths by way of increased natural angiogenic suppression. The difference is that the “set point” has been inappropriately set forward, allowing the tumor to kill the host well before the new set point is achieved (Hahnfeldt et al. 1999).

While the tumor/host relationships were earlier thought to be antagonistic (perhaps by analogy with infections), today their synergy (paradoxical “love, not war”) becomes apparent (Lichtenstein 2008). In its destructive efforts, the tumor relies on the support of normal tissues, both the immediately surrounding (Albini and Sporn 2007; Bissell and Radisky 2001; Dranoff 2004) and remote (Dolloff et al. 2007; Hayward et al. 2001; Hiratsuka et al. 2006; Kaplan et al. 2005; Karnoub et al. 2007; Nolan et al. 2007; Sawyers 2007; Williams et al. 2007; Wyckoff et al. 2007). The participants of the “rescue operation” include fibroblasts (Elenbaas and Weinberg 2001; Kalluri and Zeisberg 2006; Orimo et al. 2005), tumor-associated macrophages (Condeelis and Pollard 2006; Pollard 2004; Sahai 2007), tumor-infiltrating neutrophils (Ardi et al. 2007), stroma (Albini and Sporn 2007), bone marrow (Nolan et al. 2007), remote organs (Hiratsuka et al. 2006). Owing to the help from the outside, the tumor gets blood supply, grows, has an increased mutation rate (Gupta and Massague 2006; Sahai 2007). In cell invasion experiments, it was found that stroma fibroblasts can lay tracks in the intercellular matrix and serve as leaders for epithelial cells that followed them (Gaggioli et al. 2007). Using animal models of breast cancer metastasis, it was shown that there exist subpopulations of macrophages that provide for tumor cell extravasation, survival and subsequent growth of metastatic cells (Qian et al. 2009). Bone marrow cells exposed to cytokines secreted by the tumor migrate to target organs and prepare the niche for future metastases (Kaplan et al. 2005). The enzyme lysyl oxidase secreted by hypoxic tumor cells was found to modify the extracellular matrix and also contribute to pre-metastatic niche formation (Erler et al. 2009). These findings are supported by gene expression profiling of both epithelia and stroma at specific time points during tumor progression, which reveal sequential enrichment of genes mediating discrete biologic functions in each tissue compartment (Reuter et al. 2009).

The complex interactions between normal and tumor cells result in formation of numerous “vicious circles” that drive the tumor progression. Though microenvironment sometimes reveals “yin-yang” activities, i.e. can be, depending on circumstances, either pro- or anti-carcinogenic (Wang et al. 2004; Witz 2008), the net balance steadily develops in favor of the growing tumor.

The role in carcinogenesis of the immune system, the main defender of the organism from all invasions, is dual. At the initial stages, the adaptive immunity maintains occult cancer in an equilibrium state (Koebel et al. 2007). However, after the clone escape and tumor formation the immune system begins paradoxically to stimulate its development (Balkwill and Mantovani 2001; de Visser et al. 2006; Prehn 1994).

Thus, the oncologic process appears as program of systemic disintegration with a role of the tumor as its organizer, coordinator and pacemaker.

The question of how and why a tumor kills the organism, owing to its importance, should apparently take the central place in cancer research: its solution could help, on the one hand, to get at the root of this disease, and on the other, to find effective treatment. Strangely enough, this question does not attract the attention it deserves, and a host of questions remain. Why the death of the cancer patient is inevitable? Whether is it a side effect of tumor growth, a result of exclusively local influence on normal tissues? Or, on the contrary, is the death predetermined and caused by a certain special activity of the cancer cell, is “beneficial” and for that very reason so evolutionary conservative?

The point of view that the tumor kills by the fact of its existence seems to be self-evident (metastases, in particular, are considered to be an exhaustive explanation of the fatal outcome). This viewpoint is based probably on the fact that in vitro cultured cancer cells do not exert a negative effect on their normal neighbors, do not produce toxic products and, most likely, are not capable of doing them in vivo. At the same time, their ability to spread and form metastases is obvious. It seems natural that it is the local effects on surrounding normal tissues that cause death of the body. In some particular cases, this is what happens indeed: local effects prevail, for example, in cases of profuse bleedings, brain compression, intestine perforation or obturation, etc.

However, malignant tumor evidently exerts also a general influence on the organism. A situation of a “silent” tumor is known, for example, when there is a clinical picture of an oncologic disease but no primary locus can be found (in other words, there exist generalized manifestations but local ones are absent). The loss of weight by oncologic patients long before they are diagnosed (Grosvenor et al. 1989; Kritchevsky et al. 1991) speaks in favor of the same. The tumor growth leads to incompatible with life disturbance in the body homeostasis, which manifests itself in diverse paraneoplastic syndromes affecting almost every organ and tissue of the body (Finora 2003; Kim et al. 2003; Posner 2003; Sato et al. 2003; Tisdale 2002; Yamada et al. 2003).

A solid tumor weighting 1, 10 and 100 g results in initial, expressed and heavy clinical symptoms, respectively. It seems likely that such negligible mass should not have, in itself, any specific consequences, as is the case with benign tumors of even larger mass. Drastic discrepancy between apparent negligibility of the cause and gravity of the effects suggests that the malignant tumor is endowed with a special killer function (Lichtenstein 2005b, 2008). Owing to its universality, this function deserves to be added to the other hallmarks of cancer (Hanahan and Weinberg 2000). The killer function is a resumptive notion, which designates the ability of cancer to kill an organism (no matter how). Its special case is cachexia (the cause of death of ~20% of cancer patients), which is the most demonstrative example of distant and generalized influence of cancer on the body (Tisdale 2002).

The cancer cell is obviously not capable of producing any toxins or doing something that the normal cell is unable to do at some stage of its development (after all, they both have the same genome). Since animal cells produce a host of various biologically active compounds (cytokines, chemokines, ROS, etc.), it is possible to assume the following general mechanism of the killer function: cancer cells, possessing an ordinary set of instruments, use them in unusual combinations and/or concentrations, or at inadequate times and/or place, what brings about incompatible with life disturbances of the homeostasis. For example, the cytokine MIC-1 produced by many tumors is capable of inducing, via central mechanisms, anorexia and loss of weight (Johnen et al. 2007). The cachexia observed in many cancer patients is also due to the factors secreted by the tumor or its environment: (1) increased lipolysis is induced by lipid-mobilizing factor; (2) tissue catabolism is partially mediated by cytokine TNF-α as well as interleukins (IL)-1 and IL-6; (3) proteolysis-inducing factor directly stimulates tissue breakdown (Tisdale 2002). The comprehensive gene expression profiles of each cell type composing normal breast tissue and breast carcinomas demonstrates that extensive gene expression changes occur in all cell types during cancer progression and that a significant fraction of altered genes encode secreted proteins and receptors (Allinen et al. 2004).

The accepted paradigm does not explain the existence of killer function of cancer cell. It is impossible to understand why the appearance of a comparatively small cellular mass, regardless of its type and localization, inevitably kills the entire body (especially in view of the fact that benign tumors may sometimes be as large as several kilograms without deleterious consequences). Death of the body and preceding period of progressive decay are viewed by the accepted paradigm as a self-evident result of tumor growth. But stating a cause–effect relation between two events (tumor growth and body death) is not the same as explaining it. In the accepted paradigm, the indomitable aggression of cancer cells seems to be both meaningless and counter-productive (for some unknown reason, cancer cells always strive for self-destruction).

The new paradigm offers a simple explanation for this phenomenon: the cancer cells kill the organism because they have been created just for this purpose; the evolution having created these killers has thereby solved some problems of top priority (see above).

The notion of a malignant tumor as a specialized organ has received an additional support with the discovery of CSCs (Reya et al. 2001; Shackleton et al. 2009). The concept of CSC traces back, as was repeatedly noted, to the 150-year-old “embryonal rest” theory of cancer by Virchow, Cohnheim and Durante. Based on the similarity between cancer cells and embryonic cells, it is supposed that the tumor arises from stray embryonic cells present in an adult organism. Usually dormant, they are capable of waking up under the influence of various irritants, mainly inflammation, and giving rise to a tumor (Coussens and Werb 2002; Hendrix et al. 2007).

Current molecular and genetic data are also indicative of a similarity between cancer and embryonic cells (Strizzi et al. 2009). Thus, the transcriptional module characteristic of embryonic stem cells is activated in many cancer cells (Wong et al. 2008). Proceeding from Virchow’s statement that tumors grow by the same laws that govern embryonic development, the authors of a recent work tried to find out to what degree tumor transcriptome corresponds to that of developing tissues. Indeed, they have observed common global trends of gene expression (Naxerova et al. 2008). A common property of many tumors is the expression of C/T (cancer/testis) antigens (Simpson et al. 2005), which suggests an awakening in cancer cells of the transcription program inherent in germ cells and forming a standard malignant phenotype (immortality, immune evasion, ability to invade and metastasize, genome hypomethylation) (Old 2001).

Based on these data, a theory was advanced according to which a tumor has stem cells which are in many respects similar to normal ones: both possess the ability of self-renewal and differentiation (achieved by asymmetric division), plasticity, unlimited proliferation, ability to recreate the tissue de novo, activity of main regulators of embryonic development (Clarke and Fuller 2006; Hendrix et al. 2007; Postovit et al. 2007; Sparmann and van Lohuizen 2006). Normal mammary epithelial stem cells and breast cancer stem cells display a decreased expression of some specific microRNAs, restraining their clonogenic and tumor-initiating activities, respectively. Apparently, stem cell regulatory pathways are the same as cancer stem cell regulatory pathways (Dirks 2009; Shimono et al. 2009).

The CSC concept assumes the hierarchical structure of a tumor. The most important are CSCs, which make probably a very small fraction of the whole cell population (sometimes, their quantity is substantially higher; Adams et al. 2007; Kelly et al. 2007) and may vary in tumors of different origin (Kennedy et al. 2007). This small subpopulation governs growth of the tumor and its dissemination (Hermann et al. 2007, 2008), its selective eradication is capable, as was shown in a model system, of suppressing the growth of the tumor and its metastases (Gupta et al. 2009a). The bulk of the tumor consists of differentiated non-CSCs destined for final death and unable to recreate a tumor de novo. However, constituting the majority, non-CSCs determine the clinical picture of the disease.

The CSC concept is important in many respects. It allows us to explain difficulties of the present-day chemotherapy (stem cells possess special properties, being, in particular, more resistant to chemotherapeutic drugs) (Gupta et al. 2009a) and aim at new targets. On the other hand, this concept prompts one to reconsider the existing notion about tumorigenesis: to depart from the idea of the chaotic process of trial-and-error type and to consider it as a well familiar cell differentiation—a set of irreversible, deterministic transitions from one stable state to another (namely, the path from pluripotent CSC to differentiated non-CSCs) (Gupta et al. 2009b). As the very notion of “stemness” assumes the ability of the cell to differentiate, identification of the cancer analogue of normal stem cell suggests a corresponding interpretation: just as normal stem cells differentiate into phenotypically diverse progeny with limited proliferative potential, cancer stem cells also undergo epigenetic changes analogous to the differentiation of normal cells, forming phenotypically diverse nontumorigenic cancer cells that compose the bulk of cells in a tumor (Shackleton et al. 2009). In other words, carcinogenesis is probably not “an illness of differentiation” as usually thought, but a special differentiation, during which the cancer cell co-opts standard, ready-to-use modules: the epithelial–mesenchymal transition (Polyak and Weinberg 2009), aerobic glycolysis (Christofk et al. 2008), angiogenic switch (Bergers and Benjamin 2003), immune evasion and immunity suppression (Kim et al. 2006).

The view of tumorigenesis as a differentiation means to some extent the return to the early Virchow’s notion. Probably, cancer progenitor cells (Feinberg et al. 2006) are initially present in the body. Staying in a “waiting mode”, they are steadily exposed to internal and external mutagens what results in a gradual erosion of the system of checks-and-balances (protooncogenes and suppressor genes) and, eventually, activation of the cryptic “cancer differentiation”. The fact that precancerous stem cells are capable of developing, depending on conditions, in both the malignant and benign directions (Chen et al. 2007) indicates that there are bifurcations in development pathways that route cells along pre-determined trajectories to the alternative states, the normal and cancer phenotypes (Fig. 1). The balance between these alternative pathways apparently depends on association of the stem cell with the niche (Clarke and Fuller 2006; Li and Neaves 2006; Walkley et al. 2007). Mutations, inflammation and other factors can damage this association and favor the choice of the cancer pathway. Indeed, imaging of hematopoietic precursor division in real time has shown that the balance between symmetric and asymmetric divisions is responsive to extrinsic and intrinsic cues and, in particular, to oncoproteins (Wu et al. 2007). Fig. 1

Normal vs. cancer bifurcations in differentiation pathways. Pluripotent stem cells differentiate to form either normal or cancer stem cells (SC or CSC, respectively). By default, normal stem cell differentiation is active, while cancer differentiation is blocked by several tissue-specific barriers. As the barriers are removed by mutations or some environmental cues, cancer stem cells become gradually activated and the cryptic program is brought into action in a step-by-step manner. As a result, “differentiated” tumor cells are formed. a Carcinogenic program is blocked. b, c Gene mutations sequentially remove the barriers and make “differentiation leaps” possible. The numbers denote rate-limiting events (mutations) that are required to pass the differentiation stages. The gradual darkening of cells represents their acquisition of a cancer phenotype. Lightning arrows, mutations; arrows, passage possible; ⊥, block of cancer differentiation. (Reprinted from A.V. Lichtenstein (2008) Cancer: shift of the paradigm, Med Hypotheses, 71(6):839–850, with permission from Elsevier)