Intercellular adhesion disorders in tumorigenesis

“You have to pull the main thread

to unwind the whole tangle of contradictions”

Dan Brown

Introduction

Cancer biology research has accumulated a rich and complex body of knowledge about the molecular, cellular, and biochemical features of various human cancers. Tumorigenesis is a multistage process, and these stages reflect highly heterogeneous and chaotic changes in the genomic landscape that lead to the gradual transformation of normal human cells into highly malignant derivatives [1, 2].

Loss of proliferation control, insensitivity to growth inhibitory signals, evasion of programmed cell death (apoptosis), sustained angiogenesis, reprogramming of cellular metabolism, evasion of immune surveillance, invasion, and metastasis are the dramatic changes in cell physiology that collectively command malignant growth and represent a successful subversion of anticancer defense mechanisms [3]. However, questions remain. Which regulatory circuits must be disrupted for normal cells to become malignant? How do tumor cells link the myriad events in the host to their own destruction?

Anticancer and immunotherapeutic approaches target one or a combination of specific molecules associated with cancer, such as growth factors, receptor/adaptor molecules, cytokines/chemokines, and others. Molecular targets are derived from mutated genetic elements (e.g., DNA damage, epigenetic hypo- and hypermethylation modifications, and expression products). However, each of these targets alone is not of key importance and independent significance for cellular transformation and modulation, as well as none of the above will prevent tumor development [4-9]. 

Scientists recognize that future directions in anticancer approaches that will benefit society and be more effective should focus on the homeostatic mechanisms of the body along the neuroimmune-endocrine axis. The International Agency for Research on Cancer (IARC) has proposed further development of effective preventive strategies, given the potential for activation of nonspecific homeostatic and adaptive responses of the body. Preventive measures become important at the stages of tumorigenesis, relapse and metastasis of the tumor. In addition, it can also be useful for controlling chronic stress, increasing the effectiveness, reducing the toxicity of chemoradiotherapy, and improving the quality of life during the rehabilitation of cancer patients [10-12].

In order to unravel the tangle of contradictions, it would be great to find the decisive thread. The main focus of our review is on the disruption of adhesion regulation as a decisive factor in the tumor process.

Cell-cell junctions in epithelial tissues

In normal epithelial tissues, tightly packed and nonmotile cells function as an element of an integrated system. In contrast, tumor cells with a poorly organized mesenchymal phenotype acquire such properties as loss of differentiation, reduced intercellular adhesion, increased motility, invasive capacity, and increased resistance to apoptosis [13-15].

Differentiation and transformation of embryonic tissues into mature tissues requires the synthesis of tissue-specific proteins: e.g., liver cells need some proteins known as liver cell adhesion molecules (L-CAM), nerve cells need others known as neural cell adhesion molecules (NCAM), etc. Such proteins and cell adhesion molecules can be encoded by different genes. But the genes of these two types must act in a coordinated manner [16].

During embryonic development, the mesenchyme is transformed into the epithelial layer. The mesenchyme is a group of motile cells that are not connected to each other in any way and are not organized in space. The epithelium is a layer of highly organized cells, the basal cells of which are usually connected to the extracellular matrix by substrate adhesion molecules (SAM) (Figure 1). Epithelial cells are connected with each other by specialized contact structures, cell junction molecules (CJM). Cell adhesion molecules (CAM) play a major role in the initial stages of epithelial formation (Figure 2). Then, following CAM-to-CAM binding, specialized cell-cell junctions (e.g., tight, gap junctions, etc.) are formed. Figure 3 shows a scheme of CJM. It seems that the action of CAM genes leads to the assembly of preexisting CJM into contact structures. The sites where the membranes of both cells are parallel to each other and are 150-200 Å apart (no visible structures) are called simple junctions (nonspecialized areas of cell-cell junction) (Figure 4). Their main players are the adhesion molecules cadherins [16-18].

Figure 1. Mesenchyme and epithelial layer.

Figure 2. CAM (cell adhesion molecules) [16].

Figure 3. Scheme of specialized contact structures, CJMs (cell junction molecules).

Figure 4. Simple cell junction (nonspecialized areas of cell-cell junction). https://present5.com/tema-2-citologiya-mezhkletochnye-kontakty-organelly-yadro-delenie/

Loss of contact: additional cells

Contactin (from the cadherin family) plays an important role in histospecific intercellular interactions, as well as normal morphogenesis and tissue development. Inactivating mutations in the gene encoding contactin trigger susceptibility to hereditary cancer [19-22].

The strength of cell adhesion (Figure 5) in the liver (a) and lungs (b) of inbred mice (mutual adhesion) in the early postnatal period of completion of tissue differentiation, along with the frequency of spontaneous tumors in late ontogenesis, are associated with a hyperbolic dependence [23, 24].

Figure 5. Strength of cell adhesion in the liver at the age of 1 month (a) and in the lungs at the age of 1-5 months (b) in inbred mice, and the predisposition of these organs to the occurrence of spontaneous tumors.

It was revealed that tissue-specific contactins, when exposed during the critical period of early postnatal ontogenesis, enhance cell-cell junctions and prevent the development of genetically determined tumors, thereby reducing the frequency of their occurrence in predisposed tissue (Figure 6, Table 1) [25, 26].

Figure 6. Effect of the contactin adhesion factor (AF) in vivo on the strength of mutual adhesion of hepatocytes (F) in male CBA mice during ontogenesis. The x-axis is F (mg/cell), the y-axis is the age of mice (months) [26].

Table 1. Effect of contactin on liver tumor formation in male CBA mice after its tenfold administration

Using an electron microscope, we obtained the following picture. Elevated hydrostatic pressure causes divergence of the contact surfaces of hepatocytes, primarily in the areas of simple junction. Highly adhesive areas were detected in C57Bl mice three times more than in CBA mice (Figures 7 and 8). Under these conditions, no divergence of specialized contact structures (tight and gap junctions, desmosomes, etc.) was observed. It is likely that due to different levels of contactin, the degree of heterogeneity in simple junction can largely determine the observed differences in the strength of mutual adhesion between hepatocytes in CBA (male) and C57BL mice [27].

Figure 7. Destruction of nonspecialized areas (simple junctions) of hepatocyte contacts in C57Bl mice under the effect of elevated hydrostatic pressure as seen via an electron microscope. There are three times more areas of high adhesiveness than in CBA mice (a). With an increase in the hydrostatic load, the membrane divergence in C57Bl mice is longer, but the areas of high adhesiveness remain (b). a: Exposure to a pressure of 30 mm Hg for 15 s (× 19800); b: Exposure to a pressure of 20 mm Hg for 60 s (× 35000).

Figure 8. Destruction of nonspecialized areas (simple junctions) of hepatocyte contacts in CBA mice under the effect of elevated hydrostatic pressure as seen via an electron microscope. With an increase in the hydrostatic load, complete membrane divergence was observed in the simple junction region in CBA mice (b). a: Exposure to a pressure of 30 mm Hg for 15 s (× 43200); b: Exposure to a pressure of 20 mm Hg for 60 s (× 33000) [26].

A previously unknown phenomenon of an increase in the homophilic forces of mutual cell-cell adhesion at a decisive stage of early ontogenesis was established, which leads to the completion of the tissue homeostasis formation and a decrease in the incidence of tumors in tissues predisposed to cancer [26, 28].

Cancer is a consequence of mutation in the contactin (cadherin) gene

Reduction of cell adhesion in the target tissue can be changed due to mutations under the influence of various environmental stressors, as well as chronic stress. In genetically predisposed tissues, hemophilic intercellular adhesion is primarily impaired [29; 30]. This can be caused by the loss or suppression of one allele in the contactin gene (most likely, of the cadherin superfamily) known as zero hemizygosity state. It is important that zero hemizygosity of the contactin gene exists with a hereditary predisposition of this tissue to malignant growth.

This condition may transform into zero homozygosity (100%), since just one mutation of the existing contactin allele is sufficient, which usually occurs during ontogenesis under the impact of the environment multifactorial stress effects (Figure 9).

Figure 9. Hereditary predisposition of tissues to malignant growth.

The contactin gene is represented by two alleles in the cells of tumor-resistant tissue (the cells are homozygous for this gene) at the final stages of differentiation and transition to active functioning (Figure 10). In this case, it is virtually impossible to reduce the situation to zero homozygosity, since the probability of two consecutive mutations in the same tissue, cell and gene is extremely (approaching 0) [19, 26].

Figure 10. Normal tumor-resistant tissue.

Adhesion as a “a phoenix in the fire of malignant growth”

In epithelial tissues, contactin (E-cadherin) is a key mediator of stable cell-cell adhesion. Mutational inactivation of the contactin gene yields impairment of proliferation, differentiation, epithelial homophilic cell-cell adhesion, and cellular structure, thereby disrupting one of the central mechanisms of antitumor protection [24, 26, 31-36].

A reduction in s-ICAM expression becomes evident much later after tumor formation: it causes further fragility of cell-cell junctions. First of all, tumor cells deficient in ICAM-1 can avoid elimination via reduced expression of the corresponding ligands from leukocyte β2 integrins: lymphocyte function-associated antigen 1 (LFA-1, integrin alphaLbeta2, CD11a/CD18) and monocyte adhesion complex (Mac-1, integrin alphaMbeta2, CD11b/CD18) [37-39]. LFA-1 and Mac-1 are the main modulators of adhesion between natural killer (NK) cells or cytotoxic T lymphocytes (CTL) and cancer cells; on the other hand, they are involved in the release of cytotoxic granules that kill the tumor cells. Reduced ICAM-1 expression on tumor cells and disrupted contact between ICAM-1 and leukocyte β2 integrins contribute to the lack of adhesion/localization of CTL and natural killer NK cells, which may prevent tumor cell death [40-45].

Secondly, changes in ICAM expression also appear to play a noteworthy role in invasion and metastasis. ICAM deficiency on a tumor cell is accompanied by shifts in the spectrum of integrin α or β subunits. Cells that are capable of escaping the primary tumor (known as pioneers) and colonizing new regions in the body switch the expression of integrins from those present in normal epithelium to others, such as very late activation antigens (VLA) from the β1 integrin family. Diversity of β1 integrins can be found in many cancers such as melanoma, breast carcinoma, prostate cancer, pancreatic cancer, lung cancer [46-51]. β1 Integrin switching involves changes in their expression profile and functionality during cell detachment, thereby overcoming apoptosis and ensuring tumor cell survival and metastasis [46, 47]. Thus, increased dysregulation of adhesion leads to increased tumor evasion from immune surveillance and proliferation control [52-55]. As a result, disruption of homophilic cell-cell adhesion in tissues genetically predisposed to tumors leads to common conditions for malignancy, invasion and metastasis.

Indeed, like a phoenix vanishing during the initiation of a primary tumor by breaking contacts between identical cells, adhesion molecules reappear with a new quality (this phenomenon is known as the phoenix rising mechanism), thereby causing invasive and metastatic behavior of tumor cells. This allows the primary tumor cells to acquire motility and form metastases, which are the cause of most cancer deaths.

One of the main notions of the proposed concept is that the key role in the loss of control over cell proliferation, invasion, metastasis, and evasion of immune surveillance is played by the disruption of homophilic cell-cell adhesion (Figure 11). The argument presented below substantiates the importance of disruptions in cell-cell adhesion in carcinogenesis.

Figure 11. Expression of adhesion molecules in cancer: the phoenix rising mechanism in tumors.

1. The validity of the concept can be demonstrated by the evolutionary relationship of cadherin molecules that mediate homophilic cell-cell junctions, CJM that form specialized intercellular junctions, ICAM that regulate the recruitment of leukocyte integrin β2 from the bloodstream to the target tissue, β1 integrins that mediate invasive migration of cancer cells, proteins of the major histocompatibility complex (MHC) class I that present antigens to immune cells, IgG antibodies that redirect CTL or NK cells to the tumor, and growth factor receptors. They are gene products that evolved as a result of duplication of the original precursor, comparable to the duplication of the cadherin molecule gene.

Scientific data confirmed the importance of CAM for the evolution of multicellular organisms and the emergence of the adaptive immune system of vertebrates. Adhesion molecules provide tight contact between cells via maintaining the architectonics of tissues and organs, and also the homeostasis of the body. They can probably protect the body from the process of decay in tumor pathology (Figure 12) [16].

Figure 12. Evolutionary relationship of adhesion molecules.

2. Identifying another factor that could destroy all stages of malignancy is a complex task. Almost all connections, mechanisms, and factors necessary for the development of cancer can be integrated into a single signaling system. The determining factor in this system may be adhesion disorders at the initial stage, leading to further adhesion disorders.

3. The hypothesis can explain why tumors develop mainly in a separate organ due to the suppression of the tissue-specific adhesion factor contactin and why there are differences in the degree of metastasis due to the β1 integrin profile.

4. Reduced cell-cell junction due to impaired expression of tissue-specific cadherin (contactin) and ICAM, as well as an increase in the cell mass of the organ are specific properties of malignancy. In contrast, the development of inflammation, is associated, among other things, with a loss of cell mass and an increase in the expression of ICAM-1, ICAM-2, LFA-1, and Mac-1 in response to inflammatory mediators [56, 57]. The latter entails the activation of CD8+ lymphocytes, NK cells, etc. In rare cases of spontaneous regression of a malignant tumor, increased expression of ICAM-1 was found on the membranes of its cells with multiple infiltration of the tumor by T cells (Figure 13).

Figure13. Various types of pathologies and expression of adhesion molecules.

5. Sir Frank Macfarlane Burnet hypothesized that tumor cell neoantigens cause an immune response to cancer and subsequently formulated the immune surveillance theory. However, the theory does not explain the decrease in antitumor immunity. For instance, tumors do not arise more frequently in organs protected by the blood-brain barrier (eye structures, nervous tissue, gonads, thyroid gland) than in peripheral organs. Multiple polyclonal tumors should arise in the case of deficiency of cell-mediated immunity, but they usually are distributed in individual organs. Immunodeficient nude mice and mice of other strains have the same tumor frequency of occurrence. It is more effective to inoculate smaller volumes of tumor cells than larger ones. Some long-term immunosuppression conditions (e.g., leprosy, sarcoidosis, and uremia) do not lead to an increase in tumor incidence [58, 59].

Adhesion molecules for diagnostics and prediction of therapeutic efficacy

The efficacy of anticancer therapy can be determined by the surface expression of ICAM-1 (CD54). Determination of the expression level of leukocyte β2 integrins will allow to assess both the stage of malignancy and the efficacy of anticancer therapy (Table 2).

Table 2. The integrin family: leukocyte integrins

The prospect for determining the repertoire of β1 integrins regulating the invasive migration of cancer cells seems promising. Besides that, the source of metastases can be determined by assessing combinations of β1 integrins when the primary location of the tumor is uncertain (Table 3). The search for β1 integrin inhibitory agents (specific and nonspecific) that reduce β1 integrin signaling may be important for the regression of metastases.

Table 3. The integrin family: very late activation antigens, VLA β1 integrins (heterodimers αХ β1)

Thus, adhesion molecules that mediate intercellular interactions in the target tissue, as well as with immune effector cells and the extracellular matrix, can be studied to understand tumor progression. Also, they can act as prognostic factors for the disease and important therapeutic targets for medicinal drug action.

Potential of adhesive preparations

Adhesive drugs constitute a promising strategy for developing new approaches to treating malignant tumors and innovative methods aimed at preventing or suppressing the development of malignant processes. Transfection of ICAM-1 into human colorectal cancer cell lines increased the adhesiveness and cytotoxicity of peripheral blood mononuclear cells towards cancer cells in vitro [60]. Intratumoral injection of ICAM-2 adenoviral vector significantly inhibited tumor growth, peritoneal metastasis and survival of mice with gastric carcinoma. Histopathological data showed that many NK cells infiltrated the lesions after injection of ICAM-2 adenoviral vector [61]. Apparently, transfection of the ICAM-1,2 gene via adenoviral vector can be an effective therapy for metastasis. These are examples of specific effects of adhesive agents.

First-in-class synthetic agents that are agonists of the leukocyte β2 integrins have already been developed abroad and are in phase I clinical trials as antitumor drugs. Among them, we should mention 7HP349 (Hills Pharma, USA) and ADH-503 or Leukadherin-1 choline (Gossamer Bio, USA).

7HP349, a small molecule agonist of LFA-1, promoted preferential localization of CD8+ CTL in melanoma cells by upregulating LFA-1-mediated binding to ICAM-1 on cancer cells. 7HP349 improved the antitumor response by synergistically interacting with neutrophils in inducing cancer regression [62]. GB1275, a Mac-1 agonist, improved antitumor immunity, which led to an increase in both the number of tumor-infiltrating CTL and their cytolytic activity in pancreatic ductal adenocarcinoma, as well as breast, prostate, and microsatellite stable colorectal cancer [63].

The results of the search for nonspecific drugs with adhesive action among plant substances are remarkable. For example, the plant polyphenol resveratrol suppressed the expression of β1 integrin in the human colon carcinoma cell line HCT116, while SW480 simultaneously increased the expression of the histospecific adhesion factor, E-cadherin. Moreover, resveratrol impeded cell proliferation, colony formation, viability, and increased apoptosis in a concentration-dependent manner [64].

Our previous studies have shown that Rhodiola rosea extract components (a multitargeted natural compound with the ability to modulate various signaling pathways) exhibits adhesive properties in male CBA mice (a model of spontaneous hepatocarcinogenesis) by improving the cell-cell mutual adhesion of epithelial homophilic cells in the early postnatal period (on days 5-10 after the birth). This leads to a reduction in the frequency of spontaneous tumors in late ontogenesis. At the same time, an increase in the functional activity of T cells was noted [65].

The adhesive and antitumor efficacy of the multiphytoadaptogen complex (MPhA) was assessed in a large-scale experiment involving almost 1,000 male CBA mice. MPhA is a standardized herbal formula. It contains components of 40 plant extracts officially recognized by pharmaceutical companies (Panax ginseng, Glycyrrhiza glаbra, Eleutherococcus senticosus, Helichrysum arenarium, Aralia mandshurica, Hypericum perforatum, Rhodiola rosea, Potentilla erecta, Oplopanax elatus, Schizandra chinensis, etc.).

MPhA was used in prophylactic (during the first month of life of mice) and therapeutic (from 6 months on of life of mice, when the first tumors begin to appear, and until the natural death of the animals) modes. An increase in the number of blood cells expressing LFA-1 and Mac-1 was shown both with prophylactic and therapeutic use of MPhA. LFA-1 and Mac-1 play an important role in attracting activated СTL from peripheral blood to tumor tissue. As a result, the interaction between LFA-1 and ICAM-1 and the strong adhesion of leukocytes to target cells can be restored, facilitating the elimination of cancer cells [39, 66, 67].

Reduced levels of serum interleukin 10 (IL-10) and interleukin 6 (IL-6), as compared to control animals, were revealed [66]. IL-10 is known to inhibit T cell proliferation, antigen presentation, as well as T cell and NK cell cytotoxicity [68]. IL-6 is a pleiotropic cytokine involved in tumorigenesis by regulating multiple cancer signaling pathways, including proliferation, angiogenesis, invasiveness and metastasis [69]. Increased expression of LFA-1 and Mac-1, as well as inhibition of the corresponding interleukins by MPhA, may be useful for the elimination of cancer cells.

Immunoreactivity of experimental animals was reflected in the infiltration of spontaneous hepatocarcinomas by CD8+ CTL expressing the CD11a subunit of LFA-1 and the CD11b subunit of Mac-1 (Figure 14) [70, 71]. This may imply productive binding of LFA-1 and Mac-1 to their ICAM-1 ligand on target cells, promoting the infiltration of tumor tissue by CTL and the initiation of effector functions leading to tumor destruction [72, 73].

Figure 14. Infiltration of hepatocarcinoma lymphocytes in 22-month-old CBA mice exposed to MPhA. a: In prophylactic mode; b: In therapeutic mode. 

The interaction between cancer cells and CTL can also be controlled by one of the major neurotransmitters, dopamine (DA). DA receptors have been found on immune effector cells, including T lymphocytes [74, 75]. Direct communication between brain DA and peripheral DA is crucial in the modulation of immune function. Peripheral DA promotes differentiation and effector functions of CTL. It mediates the recruitment of these cells to the tumor microenvironment and junction with target cells, acting towards them as a toxin that suppresses cell proliferation (Figure 15) [59, 76].

Figure 15. Model of contact interactions between a cytotoxic lymphocyte and a tumor cell (adopted from [59]).

The use of MPhA in preventive and therapeutic modes contributed to the preservation of a high number of dopaminergic neurons in the brain in late ontogenesis of male CBA mice. This correlated with a decline in the incidence of tumors (by 30%), their number, and size without affecting body weight, as well as with an increase in life expectancy (by 15-25%) and quality of life in animals with normalization of the stress hormone corticosterone elevated level. The lifespans of mice in the control, prophylactic, and therapeutic groups were 22, 25, and 27 months, respectively, which correlated with the human age of 62, 70, and 75 years, respectively, when converting the age of mice to the age of humans (Figure 16) [77-81].

Figure 16. Flow chart of a large-scale experiment on the effect of multiphytoadaptogen in prophylactic and therapeutic modes on spontaneous hepatocarcinogenesis in inbred male CBA mice with high levels of cancer [81].

Summarizing the obtained results, it is possible to assume the contribution of peripheral and central adhesion mechanisms in the immune system to the control of malignant tumor formation. It should be noted that the mechanisms of tumor growth acceleration by chronic stress can be detailed due to the modulation of peripheral and central DA levels, which are directly associated with each other.

Since we registered MPhA as a parapharmaceutical agent and confirmed its harmlessness in practice, we had the opportunity to study its use in a dental clinic in patients with oral leukoplakia (OLK), which can be considered a precancerous disease. It is known that OLK transforms into squamous cell carcinoma of the oral mucosa in 75% of cases [82-84]. 

When MPhA was administered to patients with OLK, we observed an increase in ICAM-1 expression on the surface of oral mucosal epithelial cells. Also, expression of keratin 17 involved in keratinocyte proliferation was reduced, and expression of the Fas/APO-1 receptor, which activates apoptosis, was augmented. In 57% of patients, these changes correlated with a decrease in the size and density of OLK lesions. Clinical recovery was observed in 17% of cases. Compared with traditional vitamin A preparations, MPhA exhibited twice the clinical efficacy. Hence, the use of a nonspecific adhesive agent (MPhA) has shown potential for primary cancer prevention [85-90].

Increased expression of the CD11b of Mac-1 on peripheral blood cells was accompanied by a reduction in the level of tumor markers, CA19-9 and CEA, in patients with advanced gastric cancer under the effect of MPhA. As a result, the life expectancy of patients with concomitant use of MPhA was almost 2.5 times longer than that of patients in the control groups. Besides that, a decline in the elevated level of cortisol in the blood serum, an improvement in the antioxidant status, as well as normalization of cellular immunity parameters, were observed. When MPhA was added to standard treatment regimens for patients with gastric cancer, it was possible to almost double the number of polychemotherapy courses and reduce their toxic effects. A substantial decrease in sarcopenia symptoms was noted [91-93].

Thus, in experiments and in the clinic, nonspecific adhesive MPhA has been used to obtain therapeutic antitumor effects, as well as the possibility of primary, secondary and tertiary prevention of malignant neoplasms. Therefore, our research has fully proven the effectiveness of MPhA for preventive oncology.

There is no model for studying the effect of pharmaceutical agent on cadherin mutations. Hence, the antimutagenic effect of MPhA was shown on the standard Saccharomyces cerevisiae model to complete the identification of MPhA activity within the adhesion concept. The frequency of spontaneous mutations of canavanine resistance (CANR) decreased 6.4 -fold, while mutations in the ADE4-ADE8 loci were reduced by over 100 times. This is a red-white test system. Red colonies are normal. Mutant cells grow white. Addition of MPhA to the culture medium significantly reduced the number of mutant (white) colonies. MPhA reduced the frequency of direct mutations induced by UV irradiation and nitric acid in yeast cells by 3.7 times and 33 times, respectively [94].

An antimutagenic effect of MPhA on chromosomal aberrations of lymphocytes in patients with age-related benign prostatic hyperplasia was also established. Patients received MPhA in courses for several months. As a result, an almost threefold decrease in the age-related frequency of chromosomal aberrations was revealed [95, 96]. High antimutagenic effects in vitro and in humans confirmed that MPhA is an effective antimutagen, including, possibly, its efficacy against mutations of tissue-specific adhesion factors from the cadherin family.

Given modern trends in the development of anticancer and anti-aging approaches, the study of nontoxic geroprotective medicinal drugs with adhesive properties opens up their potential for further development of effective methods for the prevention and treatment of oncological and age-related diseases.

In March 2022, the World Health Organization (WHO) established the Global Centre for Traditional Medicine as a knowledge base with the mission of catalyzing “modern science with ancient wisdom for the health and well-being of the world’s people.” It is worth noting that the legal herbal medicine market in the world is $136 billion. In August 2023, the first ever WHO conference on alternative medicine was held on 17 and 18 August 2023 in Gandhinagar, Gujarat, India. Ayurveda and naturopathy, including herbal medicine, were discussed. In this context, our results are relevant and timely.

In April 2023, as part of the New Promising Antitumor Drugs conference held at Blokhin National Medical Research Center for Oncology, the Integrative Oncology Drugs section was the first ever of the kind to be held within the framework of official medical science in Russia. We dedicated this section to the 100th anniversary of Academician Anatoly A. Vorobyov, who played a decisive role in supporting and developing our scientific field. The Section Chairs were Olga A. Bocharova, Professor, DSc (Biology); Natalia V. Pyatigorskaya, Corresponding Member of the Russian Academy of Sciences, Professor, Doctor of Pharmacy; and Fatima S. Datieva, DSc (Medicine). The Conference Chairs were Ivan S. Stilidi, Academician, Professor, DSc (Medicine) and Vyacheslav S. Kosorukov, PhD (Biology).

Cancer as rapid aging of cells. Dopamine as a geroprotector, antitumor agent, and antidepressant

Disruption of intercellular communication in the corresponding target tissue is an important modifying factor of tumorigenesis that leads to loss of cell differentiation. They lose maturity and the ability to perform certain adult functions of ‘adult’ cells. Malignancy can be considered as a manifestation of the individual cells aging according to the theoretical foundations of the concept under discussion [14, 58, 59]. The problem of cancer can thus be attributed to the mysteries of birth, aging, and death. Its solution requires boundless perseverance.

However, it is still possible to try to rely on the protective functions of the body, which prevent aging and prolong life. Activation of endogenous anti-stress and geroprotective mechanisms can be effective in preventing tumor development.

Brain DA is considered a central marker of aging in the body. Sufficient DA levels support motor activity, cognitive capabilities of the brain, and the tone of internal organs and blood vessels. Long-term viability of DA neurons also safeguards longevity [58, 59, 97-100]. That is why neuroprotectors are so important!

The neuroprotective and adhesive efficacy of MPhA was assessed in male CBA mice and C57Bl mice with induced parkinsonism syndrome (age-related disorder model). When using MPhA, an increase in motor activity and a decrease in rigidity of animals were observed. MPhA maintained the level of brain DA and its metabolites, prevented the death of brain dopaminergic neurons by suppressing the level of caspase-3, reduced the content of serotonin, and impeded the formation of lipid peroxidation products, such as malondialdehyde (MDA) [101].

When examined in a neurology clinic, patients with Parkinson’s disease (PD) received two courses of treatment during three months using MPhA against the background of standard therapy, which included drugs containing levodopa.

Complex standard therapy with MPhA in patients with PD eliminated disorders of daily routine and physical activity (tremor, rigidity and bradykinesia). Normalization of immune, antioxidant and hormonal statuses was shown as well. The achieved noticeable improvement of life quality in patients with PD allow reducing the dosage of levodopa-containing medicines, which have serious side effects. MPhA acted in a nontoxic, targeted manner in the body and proved its efficacy in reducing mortality as well as maintaining the level of viable DA-producing neurons [102, 103]. Hence, this only confirms the view that DA neurons are involved in the ‘conspiracy’ that limits life [58, 59, 76].

Conclusion

High levels of brain DA support intellectual, motivational, and motor activity, enhancing adhesive defense mechanisms in the immune system of the body against defective cells that can negatively affect life expectancy. With age and with chronic stress, loss of DA neurons in the brain occurs, which entails the suppression of peripheral DA with all ensuing consequences. With loss of brain DA, the proposed paradigm regarding the key role of impaired regulation of adhesion in target tissue and immunoreactivity processes in neoplasia reveals, among other things, the stress mechanism of cancer etiology. Therefore, an important conclusion of our reasoning may be a previously unknown answer to the question of the mechanism leading to the development of malignant neoplasms as a result of chronic stress.

Loss of contact with native cells as a result of the histospecific factor mutation in the tissue leads to the formation of additional tissue cells that quickly age, losing their mature functions and connections with immune effector cells. They form a malignant tumor ready to attach to new nutrient substrates, invading the body and leading to its death. However, central dopaminergic mechanisms are capable of restoring contacts between immune effector cells and tumor cells, which can lead to effective elimination of antisocial cells, thereby preventing a lethal outcome (Figure 17).

Figure 17. Flow chart of the adhesion concept in cancer biology: local and central mechanisms (adopted from [59]).

Finally, an important conclusion is that the activation of the central and peripheral mechanisms in the body in terms of the adhesion concept the described approaches implementation creates an unambiguous and specific prospect for increasing the effectiveness of diagnostic, prophylactic and therapeutic methods, which can become another step towards solving the problems of malignant neoplasms.

The entire philosophy linking adhesion molecules with molecules of the immune and dopaminergic systems would be impossible within the framework of highly specialized studies. Only by considering the problem from broad evolutionary, genetic, embryological, immunological and other scopes, and simultaneously conducting certain studies, we can unite into a coherent whole what at first glance seems unrelated. Experimental oncology using all the means of a broad and deep scientific horizon strives to solve the problem of malignant neoplasms, which is extremely difficult and requires endless perseverance.

Funding

This study has received no external funding.

Conflict of interest

The authors declare no conflicts of interest.

Supplement 1. Photos of scientists with the greatest contribution to the formation of the theory.

“A scientific hypothesis always goes beyond

 the facts that served as the basis

 for its construction”

V.I. Vernadsky

Andrey G. Malenkov, professor, biophysicist

He introduced me to the problem of intercellular adhesive interactions in tissues at the very beginning, in my sophomore year. He planted the seed! We carried out fundamental research on adhesion, which was included in my PhD thesis. These data have become part of a larger scientific study, for which we received a Diploma for the Discovery, The Phenomenon of Increase in Adhesive Forces During Intercellular Interaction in Epithelial Tissues in Early Postnatal Period. That was 35 years ago.

Vladimir M. Bukhman (1940-2021), professor, immunologist and toxicologist

I have met him back in 1978, right after graduating from the Academy, and it so happened that he revised the concept of adhesion from the very beginning. With his erudition, Professor Vladimir Mikhailovich Bukhman, contributed greatly to the clarification of the growing understanding of adhesion via uniting a large number of phenomena into a single entity.

Rakhim M. Khaïtov (1944-2022), academician of the Russian Academy of Sciences, professor, immunologist

Director of the Research Institute of Immunology. From the height of being a great scientific and practical leader in immunology, he supported my seemingly conceited theoretical statements. Due to the warm support from Professor Rahim M. Khaïtov, in 2002, we were the first in the world to publish the opinion that “cancer is the rapid aging of tissue cells.” With gratitude to Fate and the Almighty, I recall our meetings and discussions of the adhesion theory in cancer biology.

Georgy N. Kryzhanovsky (1922-2013), academician of the Russian Academy of Medical Sciences, professor, pathophysiologist

Director of the Research Institute of General Pathology and Pathophysiology. Academician-Secretary of the Medical and Biological Department of the Russian Academy of Medical Sciences. Founder and first President of the International Society for Pathophysiology. Without him, without his support of the central dopamine paradigm, our theory would not have received actual development as the third cornerstone, along with the mechanisms of adhesion at the level of target tissues and immunity.

Nikolay P. Bochkov (1931-2011), academician of the Russian Academy of Medical Sciences, professor, geneticist

Director of the Research Institute of Medical Genetics now bearing his name. Vice President of the Russian Academy of Medical Sciences. Evidence of high antimutagenicity of the adhesive neuroprotector in our experiment performed on Saccharomyces cells in collaboration with the Institute of General Genetics, as well as in another experiment on lymphocytes of patients with benign prostatic hyperplasia performed jointly with the Institute of Medical Genetics under the supervision and with the input of Professor Nikolay P. Bochkov, fully clarified the possibility of correcting mutagenesis during adhesion dysregulation in the target tissue, which in many ways reinforced our hypothesis scientifically.

Gerald Maurice Edelman (1929-2014), American immunologist and neurophysiologist who shared the 1972 Nobel Prize in Physiology or Medicine work with Rodney Robert Porter for “discoveries concerning the chemical structure of antibodies”

Of course, he charmed me in absentia with his broad outlook and freedom of thought in publications on topobiology and the links between tissue adhesion molecules and immunity.

Аnatoly A. Vorobyov (1923-2006) Academician of the Russian Academy of Medical Sciences, immunologist, epidemiologist, microbiologist, Major General of the Medical Service

In 2023, we celebrated his 100th anniversary, dedicating scientific and popular science articles to him, as well as scientific reports at conferences. The scientific outlook of Professor Anatoly A. Vorobyov, the colossal scale of a talented scientist, doctor and teacher, as well his philosophical views on science, were the support for novel ideas problem-solving tasks.

We will always remember these scientists who are extraordinary and bright personalities! They teach us to this day!