Theory Of Carcinogenesis Research Articles

When DNA Mutations Interplay with Cellular Proliferation: A Narrative History of Theories of Carcinogenesis.

While cancer is one of the most documented diseases, how normal cells become cancerous is still debated. To address this question, in the first part of this review, we investigated the long succession of theories of carcinogenesis since antiquity. Initiated by Hippocrates, Aristotle, and Galen, the humoral theory interpreted cancer as an excess of acid, the black bile. The discovery of the circulation of blood by Harvey in 1628 destroyed the basis of the humoral theory but revived the spontaneous generation hypothesis which was also promoted by Aristotle. In 1859, the theory of microbes promoted by Pasteur demonstrated the irrelevance of this last theory and contributed to the emergence of the germ cancer theory, opposed to the cellular theory of cancer, in which cancer was supposed to be caused by microbes or transformed cells, respectively. These theories were progressively refined by the notions of initiation, promotion, and progression thanks to advances in mutagenesis and cellular proliferation. In the second part of this review, recent discoveries and paradigms in carcinogenesis, notably the role of the protein ATM, a major actor of the stress response involved in both mutagenesis and cellular proliferation, were discussed to better understand the current state of the art of carcinogenesis.

Hypothesis: hematogenous metastatic cancer cells of solid tumors may disguise themselves as memory macrophages for metastasis.

German pathologist Otto Aichel suggested, a century ago, that the cancer cell acquired its metastatic property from a leukocyte via cell-cell fusion. Since then, several revised versions of this theory have been proposed. Most of the proposals attribute the generation of the metastatic cancer cell to the fusion between a primary cancer cell and a macrophage. However, these theories have not addressed several issues, such as dormancy and stem cell-like self-renewal, of the metastatic cancer cell. On the other hand, recent studies have found that, like T- and B-/plasma cells, macrophages can also be categorized into naïve, effector, and memory/trained macrophages. As a memory/trained macrophage can enter dormancy/quiescence, be awakened from the dormancy/quiescence by acquainted primers, and re-populate via stem cell-like self-renewal, we, therefore, further specify that the macrophage fusing with the cancer cell and contributing to metastasis, belongs with the memory/trained macrophage, not other subtypes of macrophages. The current theory can explain many puzzling clinical features of cancer, including the paradoxal effects (recurrence vs. regression) of microbes on tumors, "spontaneous" and Coley's toxin-induced tumor regression, anticancer activities of β-blockers and anti-inflammatory/anti-immune/antibiotic drugs, oncotaxis, surgery- and trauma-promoted metastasis, and impact of microbiota on tumors. Potential therapeutic strategies, such as Coley's toxin-like preparations, are proposed. This is the last article of our trilogy on carcinogenesis theories.

Key models and theories of carcinogenesis

Key models and theories of carcinogenesis

Computational modeling of locoregional recurrence with spatial structure identifies tissue-specific carcinogenic profiles.

Local and regional recurrence after surgical intervention is a significant problem in cancer management. The multistage theory of carcinogenesis precisely places the presence of histologically normal but mutated premalignant lesions surrounding the tumor - field cancerization, as a significant cause of cancer recurrence. The relationship between tissue dynamics, cancer initiation and cancer recurrence in multistage carcinogenesis is not well known. This study constructs a computational model for cancer initiation and recurrence by combining the Moran and branching processes in which cells requires 3 or more mutations to become malignant. In addition, a spatial structure-setting is included in the model to account for positional relativity in cell turnover towards malignant transformation. The model consists of a population of normal cells with no mutation; several populations of premalignant cells with varying number of mutations and a population of malignant cells. The model computes a stage of cancer detection and surgery to eliminate malignant cells but spares premalignant cells and then estimates the time for malignant cells to re-emerge. We report the cellular conditions that give rise to different patterns of cancer initiation and the conditions favoring a shorter cancer recurrence by analyzing premalignant cell types at the time of surgery. In addition, the model is fitted to disease-free clinical data of 8,957 patients in 27 different cancer types; From this fitting, we estimate the turnover rate per month, relative fitness of premalignant cells, growth rate and death rate of cancer cells in each cancer type. Our study provides insights into how to identify patients who are likely to have a shorter recurrence and where to target the therapeutic intervention.

Structured Water and Cancer: Orthomolecular Hydration Therapy

It is a common practice to envision cancer exclusively as a genetic disease, however, in our perspective, changes in gene expression leading to malignancy are secondary to biochemical disturbances and at its core we consider cancer as a metabolic energetic disease. In this regard, incongruence with the concept of the bioenergetic theory of carcinogenesis, we propose structured water (EZ water), as an element that facilitates the correction of the fundamental energy disruption and the reestablishment of health. The prime approach for this therapy would be to infuse kosmotropic osmolytes by the intravenous route to improve the physiological conditions and promote the reduction of cancer growth with no side effects. By doing so, we could expect that the cells will regain their communication ability with a functioning Ras and p53 proteins and other metabolic and transcription factors. The end goal is to support the cell in overcoming its low-energy anaerobic glycolytic metabolism that favors uncontrolled growth and regain the full energetic potential of oxidative phosphorylation that supports controlled cell division and differentiation. To achieve this goal, we propose the use of metabolic correction to improve the membrane function of the mitochondria. The use of precursors, enzymatic cofactors, and a variety of biological response modifiers which includes structured water and its kosmotropic properties in enzyme dynamics are part of the metabolic correction concept.

Tumor biology: molecular genetics mechanisms of initiation, promotion and progression

For all tumors, regardless of type and tissue, there are a number of common features. These include high proliferative activity, disturbances in the mechanisms of apoptosis and "invisibility" for the cells of the immune system. At the basis of all these disorders lies a malfunction in the interaction between signaling proteins inside the cell, due to a violation of the expression of genes responsible for their synthesis. The aim of the review is to study the molecular biological mechanisms of carcinogenesis, characteristics and features of tumor cells that affect the development of the disease, progression, drug resistance and clinical results and the possibilities of targeted therapy of oncological diseases. Material and methods. The search for literature sources was carried out using PubMed, CyberLeninka, eLibrary, Google Scholar databases; the search depth was 15 years. Results. Recent works have shown the evolution of views on the classification of tumors from the point of view of the mechanisms of damage to the processes of cellular regulation and histogenesis, as well as the development of the modern theory of carcinogenesis, ideas about the mechanisms of development of tumor diseases and the prospects of modern therapies. Conclusion. The study of molecular biological mechanisms of carcinogenesis, characteristics and features of tumor cells is not only fundamental, but also of applied importance in order to predict the development of the disease, progression, drug resistance, clinical results and the possibilities of targeted therapy.

Phosphodiesterase 10A (PDE10A) as a novel target to suppress β-catenin and RAS signaling in epithelial ovarian cancer

A leading theory for ovarian carcinogenesis proposes that inflammation associated with incessant ovulation is a driver of oncogenesis. Consistent with this theory, nonsteroidal anti-inflammatory drugs (NSAIDs) exert promising chemopreventive activity for ovarian cancer. Unfortunately, toxicity is associated with long-term use of NSAIDs due to their cyclooxygenase (COX) inhibitory activity. Previous studies suggest the antineoplastic activity of NSAIDs is COX independent, and rather may be exerted through phosphodiesterase (PDE) inhibition. PDEs represent a unique chemopreventive target for ovarian cancer given that ovulation is regulated by cyclic nucleotide signaling. Here we evaluate PDE10A as a novel therapeutic target for ovarian cancer. Analysis of The Cancer Genome Atlas (TCGA) ovarian tumors revealed PDE10A overexpression was associated with significantly worse overall survival for patients. PDE10A expression also positively correlated with the upregulation of oncogenic and inflammatory signaling pathways. Using small molecule inhibitors, Pf-2545920 and a novel NSAID-derived PDE10A inhibitor, MCI-030, we show that PDE10A inhibition leads to decreased ovarian cancer cell growth and induces cell cycle arrest and apoptosis. We demonstrate these pro-apoptotic properties occur through PKA and PKG signaling by using specific inhibitors to block their activity. PDE10A genetic knockout in ovarian cancer cells through CRISP/Cas9 editing lead to decreased cell proliferation, colony formation, migration and invasion, and in vivo tumor growth. We also demonstrate that PDE10A inhibition leads to decreased Wnt-induced β-catenin nuclear translocation, as well as decreased EGF-mediated activation of RAS/MAPK and AKT pathways in ovarian cancer cells. These findings implicate PDE10A as novel target for ovarian cancer chemoprevention and treatment.

Age distribution and a multi-stage theory of carcinogenesis: 70 years on.

The Armitage Doll model demonstrates that the impact of age-dependent exposure to carcinogenic factors depends on whether the induced change occurs early, at the midpoint or late in carcinogenesis. 70 years on, updated modelling shows that their epidemiological observations still provide insight into clinical observations and their underlying molecular mechanisms.

Evolutionary View on Lactate-Dependent Mechanisms of Maintaining Cancer Cell Stemness and Reprimitivization.

Simple SummaryFor a long-time lactic acid has been considered as a toxic end-product of metabolism that cause different adverse effects. However, in recent decades a plenty of studies has refuted this suggestion and revealed many functions of lactate in living organisms. Lactic acid may be considered as one of the most ancient metabolites with signaling function and high regulatory activity. Lactate regulates key metabolic processes such as proteins expression, cells’ differentiation, inflammatory response, as well as provides stemness and unlimited cell growth, which is used by malignant tumors for their growth. Although lactatemia, observed in many cancer diseases, is possibly associated with the activation of ancient evolutionary defense mechanisms, aimed at combating metabolic disorders, and which tumors began to use for their own purposes – the acquisition of stem properties, rapid proliferation, and metastasis. In our review we aimed to summarize the accumulated knowledge about the functions of lactate in the process of carcinogenesis and to consider the possible evolutionary significance of the Warburg effect.The role of lactic acid (lactate) in cell metabolism has been significantly revised in recent decades. Initially, lactic acid was attributed to the role of a toxic end-product of metabolism, with its accumulation in the cell and extracellular space leading to acidosis, muscle pain, and other adverse effects. However, it has now become obvious that lactate is not only a universal fuel molecule and the main substrate for gluconeogenesis but also one of the most ancient metabolites, with a signaling function that has a wide range of regulatory activity. The Warburg effect, described 100 years ago (the intensification of glycolysis associated with high lactate production), which is characteristic of many malignant tumors, confirms the key role of lactate not only in physiological conditions but also in pathologies. The study of lactate’s role in the malignant transformation becomes more relevant in the light of the “atavistic theory of carcinogenesis,” which suggests that tumor cells return to a more primitive hereditary phenotype during microevolution. In this review, we attempt to summarize the accumulated knowledge about the functions of lactate in cell metabolism and its role in the process of carcinogenesis and to consider the possible evolutionary significance of the Warburg effect.

Transcriptional and post-transcriptional regulation of checkpoint genes on the tumour side of the immunological synapse

Cancer is a disease of the genome, therefore, its development has a clear Mendelian component, demonstrated by well-studied genes such as BRCA1 and BRCA2 in breast cancer risk. However, it is known that a single genetic variant is not enough for cancer to develop leading to the theory of multistage carcinogenesis. In many cases, it is a sequence of events, acquired somatic mutations, or simply polygenic components with strong epigenetic effects, such as in the case of brain tumours. The expression of many genes is the product of the complex interplay between several factors, including the organism’s genotype (in most cases Mendelian-inherited), genetic instability, epigenetic factors (non-Mendelian-inherited) as well as the immune response of the host, to name just a few. In recent years the importance of the immune system has been elevated, especially in the light of the immune checkpoint genes discovery and the subsequent development of their inhibitors. As the expression of these genes normally suppresses self-immunoreactivity, their expression by tumour cells prevents the elimination of the tumour by the immune system. These discoveries led to the rapid growth of the field of immuno-oncology that offers new possibilities of long-lasting and effective treatment options. Here we discuss the recent advances in the understanding of the key mechanisms controlling the expression of immune checkpoint genes in tumour cells.

Genomic catastrophe, the peritoneal cavity and ovarian cancer prevention.

The current theory of carcinogenesis for the deadliest of 'ovarian' cancers-high-grade serous carcinoma (HGSC)-holds that the malignancy develops first in the fallopian tube and spreads to the ovaries, peritoneum, and/or regional lymph nodes. This is based primarily on the observation of early forms of serous neoplasia (serous tubal intraepithelial lesions [STILs], and serous tubal intraepithelial carcinomas [STICS]) in the fimbria of women undergoing risk reduction surgery. However, these lesions are uncommon in the general population, confer a low risk (5%) of HGSC following their removal in at-risk women with germ-line BRCA1/2 mutations, and require 4 or more years to recur as intraperitoneal HGSC. These features suggest that isolated STILs and STICs behave as precursors, with uncertain cancer risk rather than carcinomas. Their evolution to HGSC within, or after, escape from the tube could proceed stepwise with multiple biologic events; however, it is unclear whether tubal or ovarian HGSCs encountered in the setting of advanced disease evolved in the same fashion. The latter scenario could also be explained by a 'catastrophic' model in which STICs suddenly develop with invasive and metastatic potential, overwhelming or obscuring the site of origin. Moreover, a similar model might explain the sudden emergence of HGSC in the peritoneal cavity following escape of precursor cells years before. Long-term follow-up data from opportunistic or prophylactic salpingectomy should shed light on where malignant transformation occurs, as well as the timeline from precursor to metastatic HGSC. © 2022 The Pathological Society of Great Britain and Ireland.

Profound synchrony of age-specific incidence rates and tumor suppression for different cancer types as revealed by the multistage-senescence model of carcinogenesis.

The age-specific trend of cancer incidence rates, but not its magnitude, is well described employing the multistage theory of carcinogenesis by Armitage and Doll in combination with the senescence model of Pompei and Wilson. We derived empirical parameters of the multistage-senescence model from U.S. Surveillance, Epidemiology, and End Results (SEER) incidence data from 2000–2003 and 2010–2013 for The Cancer Genome Atlas (TCGA) cancer types. Under the assumption of a constant tumor-specific transition rate between stages, there is an extremely strong linear relationship (P < 0.0001) between the number of stages and the stage transition rate. The senescence tumor suppression factor for 20 non-reproductive cancers is remarkably consistent (0.0099±0.0005); however, five female reproductive cancers have significantly higher tumor suppression. The peak incidence rate for non-reproductive cancers occurs at a younger age for cancers with fewer stages and their carcinogenic stages are of longer duration. Driver gene mutations are shown to contribute on average only about a third of the carcinogenic stages of different tumor types. A tumor’s accumulated incidence, calculated using a two-variable (age, stage) model, is strongly associated with intrinsic cancer risk. During both early adulthood and senescence, the pace of tumor suppression appears to be synchronized across most cancer types, suggesting the presence of overlapping evolutionary processes.

Mathematical Modeling of Locoregional Recurrence Caused by Premalignant Lesions Formed Before Initial Treatment.

Locoregional recurrence after surgery is a major unresolved issue in cancer treatment. Premalignant lesions are considered a cause of cancer recurrence. A study showed that premalignant lesions surrounding the primary tumor drove a high local cancer recurrence rate after surgery in head and neck cancer. Based on the multistage theory of carcinogenesis, cells harboring an intermediate number of mutations are not cancer cells yet but have a higher risk of becoming cancer than normal cells. This study constructed a mathematical model for cancer initiation and recurrence by combining the Moran and branching processes in which cells require two specific mutations to become malignant. There are three populations in this model: (i) normal cells with no mutation, (ii) premalignant cells with one mutation, and (iii) cancer cells with two mutations. The total number of healthy tissue is kept constant to represent homeostasis, and there is a rare chance of mutation every time a cell divides. If a cancer cell with two mutations arises, the cancer population proliferates, violating the homeostatic balance of the tissue. Once the number of cancer cells reaches a certain size, we conduct computational resection and remove the cancer cell population, keeping the ratio of normal and premalignant cells in the tissue unchanged. After surgery, we considered tissue dynamics and eventually observed the second appearance of cancer cells as recurrence. Consequently, we computationally revealed the conditions where the time to recurrence became short by parameter sensitivity analysis. Particularly, when the premalignant cells’ fitness is higher than normal cells, the proportion of premalignant cells becomes large after the surgical resection. Moreover, the mathematical model was fitted to clinical data on disease-free survival of 1,087 patients in 23 cancer types from the TCGA database. Finally, parameter values of tissue dynamics are estimated for each cancer type, where the likelihood of recurrence can be elucidated. Thus, our approach provides insights into the concept to identify the patients likely to experience recurrence as early as possible.

760Multi-stage models of cancer and disease

Abstract Background Since Armitage and Doll's publication of “a multi-stage theory of carcinogenesis” in 1954, the multi-stage model has underpinned our conceptual understanding of cancer. In the last few years the model has been applied to other diseases, such as Amyotrophic Lateral Sclerosis (Motor Neurone Disease), providing new insight into how the disease can arise and progress. Methods The multi-stage model is simplified and generalised. The result is a simple mathematical toolkit to describe carcinogenesis or other multi-stage models of disease, with simple formulae corresponding to pictorial diagrams of the multi-stage process. Important practical issues are described regarding the fitting of data and the use of multi-stage models to interpret results. Results Relationships between established cancer models are clarified, and derivations are simplified. We provide examples and highlight pitfalls of fitting multistage models to data. It is explained how genetic markers and the multi-stage paradigm can provide new insights into mechanisms of disease. Limitations of the model are discussed in the context of recent cancer research. Conclusions A simple mathematical recipe can convert biologically-motivated models for each step in a disease’s progression, into a mathematical model. The framework provides a mathematical toolkit to study the failure of complex systems, biological or otherwise, simplifying the formulation and interpretation of multi-stage models. Key messages Multi-stage models are increasingly easy to use and understand. When combined with big data and genetic markers for stratification, they offer a new tool for epidemiological studies.

Abstract 1213: PDE10A as a novel target to suppress Wnt/β-catenin signaling and other oncogenic pathways in ovarian cancer

Abstract Objective: A leading theory for ovarian carcinogenesis proposes that the inflammation associated with incessant ovulation is a driver of oncogenesis. Consistent with this theory, epidemiological studies have shown that nonsteroidal anti-inflammatory drugs (NSAIDs) decrease ovarian cancer risk. Previous studies suggest, however, that the antineoplastic activity of NSAIDs does not require the traditional cyclooxygenase (COX) enzyme inhibition, and rather may be exerted through phosphodiesterase (PDE) inhibition. PDEs represent a potentially unique chemopreventive target for ovarian cancer given that ovulation is regulated by cyclic nucleotide signaling. This study evaluates the effects of phosphodiesterase 10A (PDE10A) inhibition as a novel chemopreventive and therapeutic approach for ovarian cancer. Methods: We investigated the effects of PDE10A small molecule inhibitors, Pf-2545920 and MCI-030 (a novel non-COX inhibitory NSAID-derivative), and PDE10A knockout by CRISPR/Cas9 gene editing in various ovarian cancer cell lines using in vitro assays that measured cell proliferation, cell viability, cell cycle arrest, apoptosis, cell migration and invasion. Downstream signaling pathways affected by PDE10A inhibition and gene knockout (KO) were assessed by western-blotting, confocal microscopy, and RNA sequencing. Results: Analysis of The Cancer Genome Atlas (TCGA) ovarian cancer database and an institutional cohort of ovarian cancer patients revealed that high PDE10A mRNA expression was associated with significantly worse overall survival. PDE10A expression was also positively correlated with oncogenic and inflammatory signaling pathways in the TCGA dataset. PDE10A inhibition with Pf-2545920 or MCI-030 decreased ovarian cancer cell proliferation, while inducing cell cycle arrest and apoptosis. Using inhibitors to block PKA (H89) and PKG (KT5823) kinase activity, we demonstrated that the pro-apoptotic effects of PDE10A inhibition were mediated by activation of cGMP/PKG and cAMP/PKA signaling. SKOV3 and OV-90 PDE10A KO cells showed decreased colony formation, cell proliferation, and migration and invasion properties compared to their wild-type (WT) counterparts. Moreover, PDE10A inhibition decreased Wnt-induced β-catenin nuclear translocation as well as decreased EGF-mediated activation of RAS/MAPK and AKT pathways in ovarian cancer cells. RNA sequencing of SKOV3 PDE10A KO clones revealed that pathways associated with cancer, Wnt and TGF-β signaling were downregulated compared to WT control cells. Conclusions: Our data demonstrate that PDE10A has pro-tumorigenic effects in ovarian cancer cells and its high expression in ovarian cancer patients is associated with poor prognosis. Altogether, our results warrant future studies of PDE10A as a novel target for ovarian cancer chemoprevention and/or treatment. Citation Format: Rebecca M. Barber, Elaine Gavin, Alla Musiyenko, Wito Richter, Kevin J. Lee, Annelise Wilhite, Joel F. Andrews, Steve McClellan, Ileana Aragon, Antonio Ward, Xi Chen, Adam Keeton, Kristy Berry, Gary A. Piazza, Jennifer M. Scalici, Luciana Madeira da Silva. PDE10A as a novel target to suppress Wnt/β-catenin signaling and other oncogenic pathways in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1213.

A bioelectric model of carcinogenesis, including propagation of cell membrane depolarization and reversal therapies

As the main theory of carcinogenesis, the Somatic Mutation Theory, increasingly presents difficulties to explain some experimental observations, different theories are being proposed. A major alternative approach is the Tissue Organization Field Theory, which explains cancer origin as a tissue regulation disease instead of having a mainly cellular origin. This work fits in the latter hypothesis, proposing the bioelectric field, in particular the cell membrane polarization state, and ionic exchange through ion channels and gap junctions, as an important mechanism of cell communication and tissue organization and regulation. Taking into account recent experimental results and proposed bioelectric models, a computational model of cancer initiation was developed, including the propagation of a cell depolarization wave in the tissue under consideration. Cell depolarization leads to a change in its state, with the activation and deactivation of several regulation pathways, increasing cell proliferation and motility, changing its epigenetic state to a more stem cell-like behavior without the requirement of genomic mutation. The intercellular communication via gap junctions leads, in certain circumstances, to a bioelectric state propagation to neighbor cells, in a chain-like reaction, till an electric discontinuity is reached. However, this is a reversible process, and it was shown experimentally that, by implementing a therapy targeted on cell ion exchange channels, it is possible to reverse the state and repolarize cells. This mechanism can be an important alternative way in cancer prevention, diagnosis and therapy, and new experiments are proposed to test the presented hypothesis.

Overcoming the problem of the lack of an immune response to cancer: A possible haptogenic approach to cancer immunotherapy

Cancer cells possess a number of unusual features, most of which are explicable in the light of the theory of epigenetic carcinogenesis. This includes the remarkable failure of malignant cells to evoke an immunological response from the host which is ascribed to their deviant behaviour resulting from anomalous expression of normal gene products. Given this background a possible approach to eliciting a specific anti-cancer immune response is proposed which involves selective haptenation of an identifiable target protein.

Is Cancer Cell Reversion to Normalcy Possible? Un Update

Molecular biological investigations of the last decade have not been able to definitively determine the source of oncogenic transformation [1]. In recent years, the theory of carcinogenesis by CSCs has become increasingly plausible [2], but where do the CSCs come from? So far, the origin of CSCs has been obscure and controversial [3]. At first, CSCs and normal human stem cells hSCs seem to be strongly related. They have both the capacity for self-renewal and multilineage differentiation. Accordingly, CSCs were thought to originate from normal stem cell mutants, progenitor cell mutants or transiently amplifying cells of unregulated self-renewal ability [4]. Other researchers thought that CSCs originated from adult cells by de-differentiation [5-7] or by de-differentiation of mutated cells that create stem cell-like characteristics. In other words, a fully differentiated cell undergoes mutations or extracellular signals that drive it back to a stem-like state(a). Even today, the origin of CSCs is vague and ambiguous.

Regulation of breast cancer oncogenesis by the cell of origin's differentiation state.

Human breast cancer which affects 1/8 women is rare at a cellular level. Even in the setting of germline BRCA1/BRCA2, which is present in all breast cells, solitary cancers or cancers arising at only several foci occur. The overwhelming majority of breast cells (109–1012 cells) resist transformation. Our hypothesis to explain this rareness of transformation is that mammary oncogenesis is regulated by the cell of origin’s critical window of differentiation so that target cells outside of this window cannot transform. Our novel hypothesis differs from both the multi-hit theory of carcinogenesis and the stem/progenitor cell compartmental theory of tumorigenesis and utilizes two well established murine transgenic models of breast oncogenesis, the FVB/N-Tg (MMTV-PyVT)634Mul/J and the FVB-Tg (MMTV-ErbB2) NK1Mul/J. Tail vein fibroblasts from each of these transgenics were used to generate iPSCs. When select clones were injected into cleared mammary fat pads, but not into non-orthotopic sites of background mice, they exhibited mammary ontogenesis and oncogenesis with the expression of their respective transgenes. iPSC clones, when differentiated along different non-mammary lineages in vitro, were also not able to exhibit either mammary ontogenesis or oncogenesis in vivo. Therefore, in vitro and in vivo regulation of differentiation is an important determinant of breast cancer oncogenesis.

Cell functioning in norm and pathology in terms of the activity paradigm: Oncogenesis

Over the past years many theories of carcinogenesis have been developed. Nowadays, there are two prevalent theories of carcinogenesis – two-hit hypothesis, which considers mutations as the main factor in malignization and tissue hypothesis, which considers tissue homeostasis disruption for providing cells transformation. Both of these theories explain cancer origin basing on principles of the reactivity paradigm. This paradigm emphasizes role of different stimuli in malignization. However, this approach does not provide us with sufficient support in progress towards either understanding of cancer origin or effective treatment strategies.In contrast to the reactivity paradigm, we intend to explain oncogenesis within the activity paradigm. Upon this approach, cells’ activity is goal-directed and is determined by a future event – the adaptive result. The adaptive result is a proper interaction between the cell and its environment, which provides the cell with required metabolites. To achieve this result cells have to cooperate with each other and synchronize their needs. If cells fail to satisfy their metabolic ‘needs’ they have to reorganize their activity. This results in morpho-functional restructuring of cells. Summing up, we consider carcinogenesis to be a part of goal-directed adaptive activity of cells. Morphological and genetic atypia of cancer cells is a variant reorganization of cells’ activity. Consequently, for better treatment, we should bring both transforming cells and their microenvironment to a novel cooperation and reorganization of their activity.