The Theory of Carcino-Evo-Devo and Its Non-Trivial Predictions.

To explain the sources of additional cell masses in the evolution of multicellular organisms, the theory of carcino-evo-devo, or evolution by tumor neofunctionalization, has been developed. The important demand for a new theory in experimental science is the capability to formulate non-trivial predictions which can be experimentally confirmed. Several non-trivial predictions were formulated using carcino-evo-devo theory, four of which are discussed in the present paper: (1) The number of cellular oncogenes should correspond to the number of cell types in the organism. The evolution of oncogenes, tumor suppressor and differentiation gene classes should proceed concurrently. (2) Evolutionarily new and evolving genes should be specifically expressed in tumors (TSEEN genes). (3) Human orthologs of fish TSEEN genes should acquire progressive functions connected with new cell types, tissues and organs. (4) Selection of tumors for new functions in the organism is possible. Evolutionarily novel organs should recapitulate tumor features in their development. As shown in this paper, these predictions have been confirmed by the laboratory of the author. Thus, we have shown that carcino-evo-devo theory has predictive power, fulfilling a fundamental requirement for a new theory.

Mammalian tumor-like organs. 2. Mammalian adipose has many tumor features and obesity is a tumor-like process.

BACKGROUND: In previous publications, the author developed the theory of carcino-evo-devo, which predicts that evolutionarily novel organs should recapitulate some features of tumors in their development. MAIN TEXT: Mammalian adipose is currently recognized as a multi-depot metabolic and endocrine organ consisting of several adipose tissues. Although lipid-storing cells and proteins are ancient, the adipose organ as a whole is evolutionarily novel to mammals. The adipose expansion has remarkable similarities with the growth of solid tumors. These similarities are the following: (1) The capability to unlimited expansion; (2) Reversible plasticity; (3) Induction of angiogenesis; (4) Chronic inflammation; (5) Remodeling and disfunction; (6) Systemic influence on the organism; (7) Hormone production; (8) Production of miRNAs that influence other tissues; (9) Immunosuppression; (10) DNA damage and resistance to apoptosis; (11) Destructive infiltration in other organs and tissues. These similarities include the majority of "hallmarks of cancer". In addition, lipomas are the most frequent soft tissue tumors, and similar drugs may be used for the treatment of obesity and cancer by preventing infiltration. This raises the possibility that obesity, at least in part, may represent an oncological problem. The existing similarities between adipose and tumors suggest the possible evolutionary origin of mammalian adipose from some ancestral benign mesenchymal hereditary tumors. Indeed, using a transgenic inducible zebrafish tumor model, we described many genes, which originated in fish and were expressed in fish tumors. Their human orthologs LEP, NOTCH1, SPRY1, PPARG, ID2, and CIDEA acquired functions connected with the adipose organ. They are also involved in tumor development in humans. CONCLUSION: If the hypothesis of the evolutionary origin of the adipose organ from the ancestral hereditary tumor is correct, it may open new opportunities to resolve the oncological problem and the problem of the obesity epidemic. New interventions targeting LEP, NOTCH1, SPRY1, PPARG, ID2, and CIDEA gene network, in addition to what already is going on, can be designed for treatment and prevention of both obesity and tumors.

Mammalian tumor-like organs. 1. The role of tumor-like normal organs and atypical tumor organs in the evolution of development (carcino-evo-devo).

BACKGROUND: Earlier I hypothesized that hereditary tumors might participate in the evolution of multicellular organisms. I formulated the hypothesis of evolution by tumor neofunctionalization, which suggested that the evolutionary role of hereditary tumors might consist in supplying evolving multicellular organisms with extra cell masses for the expression of evolutionarily novel genes and the origin of new cell types, tissues, and organs. A new theory-the carcino-evo-devo theory-has been developed based on this hypothesis. MAIN TEXT: My lab has confirmed several non-trivial predictions of this theory. Another non-trivial prediction is that evolutionarily new organs if they originated from hereditary tumors or tumor-like structures, should recapitulate some tumor features in their development. This paper reviews the tumor-like features of evolutionarily novel organs. It turns out that evolutionarily new organs such as the eutherian placenta, mammary gland, prostate, the infantile human brain, and hoods of goldfishes indeed have many features of tumors. I suggested calling normal organs, which have many tumor features, the tumor-like organs. CONCLUSION: Tumor-like organs might originate from hereditary atypical tumor organs and represent the part of carcino-evo-devo relationships, i.e., coevolution of normal and neoplastic development. During subsequent evolution, tumor-like organs may lose the features of tumors and the high incidence of cancer and become normal organs without (or with almost no) tumor features.

Correction to: Evolutionarily novel genes are expressed in transgenic fish tumors and their orthologs are involved in development of progressive traits in humans.

[This corrects the article DOI: 10.1186/s13027-019-0262-5.].

Evolutionarily novel genes are expressed in transgenic fish tumors and their orthologs are involved in development of progressive traits in humans.

ABSTRACT: Earlier we suggested a new hypothesis of the possible evolutionary role of hereditary tumors (Kozlov, Evolution by tumor Neofunctionalization, 2014), and described a new class of genes - tumor specifically expressed, evolutionarily novel (TSEEN) genes - that are predicted by this hypothesis (Kozlov, Infect Agents Cancer 11:34, 2016). In this paper we studied evolutionarily novel genes expressed in fish tumors after regression, as a model of evolving organs. As evolutionarily novel genes may not yet have organismal functions, we studied the acquisition of new gene functions by comparing fish evolutionarily novel genes with their human orthologs. We found that many genes involved in development of progressive traits in humans (lung, mammary gland, placenta, ventricular septum, etc.) originated in fish and are expressed in fish tumors and tumors after regression. These findings support a possible evolutionary role of hereditary tumors, and in particular the hypothesis of evolution by tumor neofunctionalization. RESEARCH HIGHLIGHTS: Earlier we described a new class of genes that are tumor-specifically expressed and evolutionarily novel (TSEEN). As the functions of TSEEN genes are often uncertain, we decided to study TSEEN genes of fishes so that we could trace the appearance of their new functions in higher vertebrates. We found that many human genes which are involved in development of progressive traits (placenta development, mammary gland and lung development etc.,) originated in fishes and are expressed in fish tumors.

Oncogenes, tumor suppressor and differentiation genes represent the oldest human gene classes and evolve concurrently.

Earlier we showed that human genome contains many evolutionarily young or novel genes with tumor-specific or tumor-predominant expression. We suggest calling such genes Tumor Specifically Expressed, Evolutionarily New (TSEEN) genes. In this paper we performed a study of the evolutionary ages of different classes of human genes, using homology searches in genomes of different taxa in human lineage. We discovered that different classes of human genes have different evolutionary ages and confirmed the existence of TSEEN gene classes. On the other hand, we found that oncogenes, tumor-suppressor genes and differentiation genes are among the oldest gene classes in humans and their evolution occurs concurrently. These findings confirm non-trivial predictions made by our hypothesis of the possible evolutionary role of hereditary tumors. The results may be important for better understanding of tumor biology. TSEEN genes may become the best tumor markers.

The Role of Heritable Tumors in Evolution of Development: a New Theory of Carcino-evo-devo.

The hypothesis of evolution by tumor neofunctionalization (the "main hypothesis") describes the possible role of hereditary tumors in evolution. The present article examines the relationship of the main hypothesis to other biological theories. As shown in this paper, the main hypothesis does not contradict to the existing biological theories, but fills the lacunas between them and explains some unexplained (or not completely understood) questions. Common features of embryonic development and tumorigenesis are described by several recognized theories. Similarities between normal development and tumorigenesis suggest that tumors could participate in the evolution of ontogenesis and in the origin of new cell types, tissues and organs. A wide spectrum of non-trivial explanations and non-trivial predictions in different fields of biology, suggested by the main hypothesis, is an indication of its fundamental nature and the potential to become a new biological theory, a theory of the role of tumors in evolution of development, or carcino-evo-devo.

Expression of evolutionarily novel genes in tumors.

The evolutionarily novel genes originated through different molecular mechanisms are expressed in tumors. Sometimes the expression of evolutionarily novel genes in tumors is highly specific. Moreover positive selection of many human tumor-related genes in primate lineage suggests their involvement in the origin of new functions beneficial to organisms. It is suggested to consider the expression of evolutionarily young or novel genes in tumors as a new biological phenomenon, a phenomenon of TSEEN (tumor specifically expressed, evolutionarily novel) genes.

Study of tumor-specific expression of some evolutionary new genes.

In this paper we have showed that evolutionary new genes DCD1(Dermicidin), LINC00309 (Long intergenic non-protein coding RNA 309) and CLLU1(Chronic lymphocytic leukemia up-regulated 1) have tumor-specific expression profile. Along with our previously published results this confirms the existence of the phenomenon of TSEEN (Tumor-Specifically Expressed, Evolutionarily Novel).

The novelty of human cancer/testis antigen encoding genes in evolution.

In order to be inherited in progeny generations, novel genes should originate in germ cells. Here, we suggest that the testes may play a special "catalyst" role in the birth and evolution of new genes. Cancer/testis antigen encoding genes (CT genes) are predominantly expressed both in testes and in a variety of tumors. By the criteria of evolutionary novelty, the CT genes are, indeed, novel genes. We performed homology searches for sequences similar to human CT in various animals and established that most of the CT genes are either found in humans only or are relatively recent in their origin. A majority of all human CT genes originated during or after the origin of Eutheria. These results suggest relatively recent origin of human CT genes and align with the hypothesis of the special role of the testes in the evolution of the gene families.

[Hyperplastic skin growth on the head of goldfish--comparative oncology aspects].

Dynamics of development and morphology of hyperplastic skin lesions ("hoods") on the head of goldfish, which were bred using artificial selection for more than thousand years, were studied. During monitoring of hundred fishes, at the age of 6 months "hoods" were found in 39.5%, among 14 months-old fishes in 60,7%. Morphologic examination of "hoods" on various stages of development revealed epithelial hyperplasia with increased clear mucous cells number, dermis thickening and oedema. On later stages developed papillomatous outgrowth and areas of epithelial intrusion. The comparative oncology analysis allow to hypothesize these skin growth to be a genetically determined benign neoplasm. This is the first example of artificially selected neoplasm described in the literature. It supports our hypothesis of the possible evolutionary role of tumors.

Morphological changes in human skin melanoma treated by high-energy pulsed neodymium laser radiation.

PURPOSE: The neodymium (Nd) laser irradiation has been successfully applied to the treatment of slightly elevated skin melanoma. At the same time the histologic aspects of such a treatment have not been precisely investigated. The aim of this study was to retrace the histological features in human primary cutaneous melanomas after 1060 nm high energy mono pulsed Nd laser treatment in the dynamic healing of the affected tissues. METHODS: Histologic analysis of cutaneous melanomas irradiated by Nd laser was carried out. Tissue specimens were taken before and immediately after exposure to laser and 1 hour, and 1, 2 and 3 days after wards. Also the wounds that appeared after the scab fell off and the scars formed following laser irradiation were also the subject of histologic analysis at 2, 4 and 6 months post-treatment. RESULTS: The Nd laser irradiation caused coagulation necrosis of melanoma, epidermis and dermis with skin appendices and superficial layers of subcutaneous fatty tissue. Foci of laser destruction were characterized by strict locality and efficient separation from the adjacent tissues, by the presence of stasis, thrombosis and coagulation of blood and lymphatic vessels. There was an increase of lymphocytes, macrophages and histiocytes in the area damaged by laser as well as in wounds and scars. CONCLUSION: The pulsed Nd laser induces acute photothermal damages of melanoma tissue, which differs from the usual thermal lesions and the most critical difference of the effect of this modality is gain of immunocompetent cells in the affected tissue after laser beam application.

[Locus HS.633957 expression in human gastrointestinal tract and tumors].

Human locus HS.633957 corresponds to its namesake cluster in the UniGene database http:/www.ncbi.nlm.nih.gov/unigene. It is located on chromosome 7 and is 3.7 tpn in size. It does not seem to encode proteins nor has its function been identified. According to bioinformation evidence, its expression is tumor-specific. PCR assay on kDNA samples from different intact human tissues detected its slight expression in liver, heart, embryonal brain and kidney as well as in a wide spectrum of tumors. This work features locus Hs.633957 expression in different parts of human gastrointestinal tract and tumors.

[Tumor-specific expression of PBOV1, a new gene in evolution].

We identified mRNA of the newly discovered gene PBOV1 in a multitude of samples from tumors of the brain, lung, liver, gallbladder, colon, small intestine, mammary gland, uterus, ovary, ureter, adrenals, parotid, thymus and spleen. However, out of 29 intact adult and 8 fetal tissues, only pancreas was characterized by weak expression of the gene. Our results demonstrated that the PBOV1 gene expression is tumor-specific and has a potential as tumor marker. It is worth mentioning that we had predicted that property on the basis of available evolutionary data.

High-energy neodymium laser radiation for the treatment of face cutaneous melanoma.

This study retrospectively evaluated the curative efficacy of two powerful pulsed Neodymium (Nd) lasers (lambda = 1060 nm, pulse duration 1 and 4.5 msec, maximum pulse energy 700 and 1000 J, respectively) for the treatment of 47 patients with histologically confirmed stage I cutaneous melanoma of the face who were followed-up 5 years and more. The estimated 5-year survival rate was 82.9%. Regional and distant metastases developed in 23.4% of the patients. There were no cases with local recurrences. High-energy pulsed Nd laser radiation is effective in treating flat and / or slightly raised cutaneous stage I facial melanomas, while the therapeutic result is also accompanied by positive cosmetic result.

[The study of characteristics of overdose among users of opioid drug injections].

Overdose is a serious problem as for people addicted to opioid drug injections (ODI) as well as for the community in general. To study characteristics of overdose, authors examined 60 ODI users and analyzed 27 overdose death cases. It has been shown that overdose is rather common among ODI users. Fatal and nonfatal overdoses most frequently take place among men at home or in the street. People often did not receive sufficient help in the overdose situation. We confirm the role of alcohol, long abstinence and variability in drug quality in the development of overdose. Witnesses of overdose in other users reported more health problems, family and social relations, were more concerned with their own and others risk in future compared to those reporting no overdose. Additional predictors were determined: a higher number of overdoses in the past; disturbances of family relations and somatic disorders. Mental disorders predicted the opioid overdose risk among ODI users. ODI users are interested in counseling and training to prevent overdose. Family psychotherapy and early diagnosis of comorbid disorders may be important ways of overdose prevention.

The possible evolutionary role of tumors in the origin of new cell types.

The ability of tumor cells to differentiate in combination with their ability to express genes that are not expressed in normal tissues, may result in the emergence of new cell types in evolution. Tumors may play an evolutionary role by providing conditions (space and resources) for the expression of newly evolving genes. Genetically or epigenetically predetermined tumors at the early stages of progression, benign tumors, and some tumor-like processes in invertebrates and plants, all of which are modes of excess cell growth which provide evolving multicellular organisms with extra cell masses, are considered as potentially evolutionarily meaningful. Malignant tumors at the late stages of progression, however, are not. The preexisting cell types of multicellular organisms had restricted potential for the expression of newly evolving genes. Because of regulation and gene competition, some of the newly evolving genes may stay silent. Multicellular organisms would need excess cell masses for the expression of newly evolving genes. The preexisting cell types cannot provide such excess cell masses because of limitations imposed on the number of possible cell divisions. Tumors could provide the evolving multicellular organisms with the excess cell masses for the expression of newly evolving genes. We suggest that tumors could be a sort of proving ground (or reservoir) for the expression of newly evolving genes that originate in the course of genome evolution in the DNA of germ cells (i.e., not in tumor cells themselves). The case in which the expression of a newly evolving gene in tumors results in the origin of a new function would be associated with the origin of new feedback and regulatory circuits, as in root nodules in legumes and macromelanophores in Xiphophorus fishes. Tumor cells would differentiate, resulting in a new cell type for the given multicellular species. This cell type would be inherited because of epigenomic mechanisms similar to those in preexisting cell types. Populations of tumor-bearing organisms with genetically or epigenetically programmed tumors could represent the transition between established species of organisms at different stages of progressive evolution. Experimental confirmation of the prediction of the hypothesis of evolution by tumor cells differentiation concerning the expression of evolutionarily new genes and/or silent (neutrally evolving) sequences in tumor cells is presented.

[Expression of transcripts related to the cluster HS.633957 in human normal and tumor tissues].

Using computational methods for analysis of electronic databases we identified a number of human nucleotide sequences expressed predominantly in tumors. We experimentally studied one of the sequences, which is related to the UniGene database cluster Hs.633957 and located near the telomere in the chromosome 7p22.3. All the RNA sequences of the cluster Hs.633957 are non-coding and their role was not described yet, but expression pattern of the locus makes it theoretically and practically interesting. Here we studied expression of the sequence Hs.633957 in various normal and tumor tissues using reverse transcription polymerase chain reaction. Of all the normal adult tissues studied weak expression was only identified in heart and liver. It was also identified in embryonic brain and kidney. Locus Hs.633957 is expressed in tumors of various tissue origin including tumors of lung, intestines, breast, stomach, cervix, lymph nodes and others. Thus the Hs.633957 locus is expressed predominantly in tumors and may be considered a prospective tumor marker.

Sexually transmitted infections, sexual risk behaviors and the risk of heterosexual spread of HIV among and beyond IDUs in St. Petersburg, Russia.

AIMS: This study investigates whether sexual transmitted behaviors and infections (STIs) among injection drug users (IDUs) may promote the spread of HIV among and beyond IDUs in Russia. METHODS: We conducted a cross-sectional survey of behavior and tested for STIs in a convenience sample of 159 IDUs in St. Petersburg, Russia. RESULTS: The median age was 27 and 57% were male. Almost all were sexually active, half had casual partners and 40% reported > or =2 sex partners in the previous 3 months. Of those who answered, 81% reported sex without condoms, 44% reported having sex with at least one partner who was not an IDU. Of 139 (87%) subjects who were actively injecting, 29% reported receptive syringe sharing. Twenty percent of subjects were seropositive for HIV-1 and 42% of HIV-1-negative subjects tested positive for an STI. CONCLUSIONS: The sample exhibited high levels of sexual risk behaviors and STIs, and a large proportion had sexual partners who were not IDUs. This population requires comprehensive interventions that ensures access to condoms and sterile injection supplies and that encourage safer sexual behaviors in an attempt to keep sexual transmission of HIV low.