Oncopathology

The genie we let out of the bottle. Interview with Academician of the Russian Academy of Sciences L. Ashrafyan

Anastasia Ibragimova, "Scientific Russia"

Cancer claims the lives of millions of people every year. He spares neither young nor adults, neither men nor women. Cancer appears spontaneously, does not always allow itself to be diagnosed quickly, and therefore it is often detected already in the phase when it becomes quite difficult to fight this disease. This was told to us by Lev Andreevich Ashrafyan, Academician of the Russian Academy of Sciences, oncogynecologist, obstetrician-gynecologist, Honored Doctor of the Russian Federation, Director of the Institute of Oncogynecology and Mammology of the National Research Center of Obstetrics, Gynecology and Perinatology. Academician V.I. Kulakov of the Ministry of Health of the Russian Federation.

— Lev Andreevich, tell us, please, what is the reason for the high cancer incidence? 

— The increase in cancer incidence has been noted since the middle of the last century. This is partly due to two global processes: an increase in life expectancy and the growth of the global economy. It was economic development that ensured the progress of medicine and the pharmaceutical industry. This made it possible to radically change the spectrum of major diseases that form the main cause of mortality. Acute and chronic infectious diseases were replaced by those associated with the aging program (atherosclerosis, diabetes, hypertension, obesity, strokes, heart attacks), but first of all — malignant tumors.

Age has become a very important risk factor. And the more we increase life expectancy, the more we will face an increase in oncological diseases in the population. But why?

The causes of the development of a malignant tumor are diverse. The ultimate target of numerous causes is a gene whose function changes dramatically, and we call this a mutation.

The number of countries in which cancer ranked first (57 countries — blue), second (55 countries — blue), third (23 countries — orange) and fourth (48 countries — red) among the leading causes of death in 2019 according to the World Health Organization.

There are direct factors that can do this, for example, radiation exposure, chemical carcinogens. But the function of the gene can be changed without structural disorders. Such a change is classified as an epigenetic modification. Any oncological process is a violation of the program of cell function due to genetic and epigenetic rearrangements. The longer a person lives, the more likely these changes are to accumulate. Modern civilizational achievements further increase the likelihood of these breakdowns, forming pathophysiological processes in which carcinogenesis is easily realized (metabolic syndrome, stress, quality and nature of nutrition, adynamia and much more). It is especially necessary to highlight the metabolic syndrome with its diverse symptom complex, which forms the main risks of oncological diseases of the female reproductive system. 

The woman has dramatically changed her lifestyle, hormonal physiology has changed significantly. On average, menstruation begins at 12-13 years old, and ends at 52-53 years old. And this is about 40 years of the reproductive period. But during these 40 years, a woman gives birth 1-2 times on average and breastfeeds no more than 3-5 months. Sexual debut — in 14-15 years, and the first birth — in 30-33 years. From this short information of a woman's anamnesis, many important and, unfortunately, common facts that contribute to the development of many oncological diseases in women follow.

Can you imagine, because in the last and the century before last, a woman by the age of 18 already had at least two children, and by the age of 25 — 4-6 children. And she breastfed for a year and a half, or even more. Ask your friends, those who have already given birth, what was the duration of breastfeeding? You will find out that some have been fed either for three months or not at all.

When a person departs from his nature, when he changes the normal, evolutionarily built pattern of his life, and also if we add improper nutrition, inactivity, I'm not talking about the spiritual state of a person, all this contributes to the development of many diseases, including malignant ones. After all, everything is tied to metabolism and genetics. So we woke up, let the genie out of the bottle, and not even one.

If we talk about how to go further in life and what to do with it, then we must understand that a modern person needs to reduce, or better eliminate, tobacco use, eat rationally, increase physical activity and try to find spiritual comfort.  And yet, taking into account the likely risks of oncological and cardiovascular diseases, it is necessary to competently build their prevention. Fortunately, modern medicine has formed a system for their effective prevention.  Americans are one of the few who have proved this expediency in practice, reducing mortality from cardiovascular diseases by 27% over the past 15-20 years.

It is good that a large number of fitness halls have appeared, people have begun to understand that in winter it is necessary to ski, in summer - to run. But you have to do it all your life. We are already so rebuilt in our biochemistry that as soon as we start eating excessively and moving a little again, the body mass index increases rapidly, shortness of breath appears, and so on and so forth.

Illustration of body mass index indicators. To calculate the body mass index, it is necessary to divide the body mass index in kilograms by the height index in meters squared. For example, if a person's weight is 85 kg and height is 164 cm, then BMI = 86:(1,64*1,64)=31, 6.

We have already said that the patterns (or mechanisms) of many oncological processes are associated with old age.

According to the figurative expression of Robert A. Gatenby, Robert J. Gillis and Joel S. Brown, the human body is playing with the "fire of evolution". The authors consider the development of cancerous tumors as an evolutionary inevitability [1].

In the 1990s, interesting post-mortem (after the death of a person) studies of the mammary glands in women and the prostate gland in men who died in car accidents were conducted. In 39% of women aged 40 to 50 years in the mammary gland and in 48% of men aged 55-65 years in the prostate gland, cancer in the zero stage was detected [2].

— What is the zero stage? When did cancer cells start forming, but not enough of them?

— The zero stage is about 108 cells. Unfortunately, today only with some localizations it is possible to fix this stage of the malignant process. This data is extremely important. They indicate a certain pattern with which a person enters the sixth decade. There is another understanding behind the understanding of this: modern preventive medicine should radically revise the principles and indications for the prevention of cancer morbidity and transfer it to the rails of effective and active technologies or measures.

The development of a tumor on the example of the stomach.

— A person does not feel this zero stage in any way?

— Yes, as a rule, he can't feel it. But for most tumors, the development of cancer is preceded by various processes, most often benign, chronic.

— And if a person with stage zero cancer begins to think about his health, engage in prevention, will the cancer continue to progress or stop developing?

— Evolutionarily, it is so laid down that the life of a person as a representative of a biological species is finite. One generation replaces another. This is the logic of life and there is no getting away from it.

Firstly, many cancers in the zero stage can remain dormant for a long time (in hibernation) and not go into invasive growth. We do not know by what laws and reasons the invasive stage of the tumor process develops. Cancer science is trying to unravel these mechanisms. The difficulties lie in the fact that oncology is perhaps the only medical discipline that fights not with deviations from the norm and not with the errors of nature, but with nature as such, since it fights with a natural biological phenomenon. In this respect, oncology is close to gerontology, which also struggles with nature, with the natural phenomenon of aging.

Secondly, even at the stage of the zero stage, effective prevention can postpone the development of the tumor indefinitely. But even if this cannot be done. A patient who is on preventive therapy has a chance of early detection of the oncological process, unlike someone who neglects prevention.

One of the important criteria in oncology is prognosis. We are able to assume that out of 100 patients with a malignant process will live for 5 years, let's say 80. But we are not able to do it by name. It is not uncommon for a patient to die very quickly with the first stage of cancer, and with the fourth stage he lives for a long time. We know a lot about the malignant process, but, alas, we do not know much more. Sometimes a fight between a doctor and a tumor process resembles a chess tournament, where the disease is a grandmaster, and the opponent is a player who only yesterday learned how the pieces move.

I still have to say such a sad thing. Over the past 50 years, we have made little progress in the long-term treatment of the patient. As a rule, we cure only a third of patients within 5 years. And we lose half of the patients during this time. There are other 20% of patients who are treated for a long time, they live during this time, constantly receiving one or another antitumor therapy. Yes, we have achieved some success in the treatment of a number of localizations, which are indicated in the statistics of the 5-year follow-up period, compared with the data of the 70s of the twentieth century. However, when they began to analyze the survival of patients for longer (10-year) periods, it became clear that we returned to the same data that took place in the 70s. 

It is very difficult to treat an already formed oncological process. It is better and easier to warn him. In addition to the already well-known preventive technologies, the general level of national culture, those public institutions and rules that motivate society and its individual member to maintain health and active longevity are of great importance.  

— Lev Andreevich, lung cancer is detected more often in one year, breast cancer in another. What is the reason for the difference in the leaders in morbidity?

— Lung cancer has been the leading cancer incidence in the world for a long time.  And this process was largely due to the high level of tobacco smoking in the world. After the link between tobacco and lung cancer became apparent, many countries took active steps in the prevention of lung cancer. They managed to reduce tobacco use many times, which became the main reason for the decrease in morbidity. On the other hand, metabolic syndrome, hormonal disorders, infections continue to actively affect women's and men's reproductive health. According to the results of Global cancer statistics 2020 [3], breast cancer in women and prostate cancer in men really came out on top.  In part, I have already said why this is happening.

Let's touch once again on the topic of obesity. Why is adipose tissue so important in the problem of the growth of cancer incidence? Today it is proved that the function of adipose tissue changes with age. In its "bowels" many biochemical processes begin to change.  In particular, adipocytes, fat cells, are increasingly producing a wide range of biologically active molecules: estrogenic, androgenic metabolites, pro-inflammatory cytokines, hormones, etc.

Adipose tissue, figuratively speaking, becomes a "metabolite factory" and a zone of chronic inflammation, where the spectrum of pro-inflammatory cytokines is close to the cytokine panel during initial carcinogenesis.

The role of metabolites is well known and studied today. Metabolites play a huge role for both men and women. Probably, a lot of women noticed that at the age of 25-30 they could easily lose weight: thanks to a diet, a little jog or exercise. And at the age of 50, such a "focus" it is no longer possible, because the function of adipose tissue has changed. You can't make her leave so easily anymore, it takes time, effort, and so on.

More than 15 years ago, we conducted a study that showed that in all variants of cancer of the reproductive organs, there is a multiple increase in such an aggressive metabolite as 16a-hydroxyestrone (16a-OH). This is especially noted in breast cancer. For a multi-targeted effect on breast tumor cells, including the suppression of 16a-OH synthesis, a special drug was subsequently created.

— In one of the interviews, you said that the cancer process and the development of the embryo have very similar mechanisms. Please explain.

— There are a lot of similarities between the initial carcinogenesis and the development of the embryo. The development of the embryo is associated with the egg and sperm, and these are, in fact, stem cells. The tumor also originates from a primary malignant stem cell.  At the initial stages, both the tumor and the blastocyst have a spheroid shape. Further, a trophoblast is formed in a certain place in the embryo, invasion and formation of the placenta begins. The same zone of legitimate development occurs in the tumor, and invasion begins. You will not find a single marker in the course of embryogenesis that would not be present during the development of the tumor process.

Both with the development of the fetus and with the development of the tumor, the body retains immunological tolerance, which by the time of delivery develops into an immunological conflict and becomes part of the mechanism of childbirth, and with a malignant process — part of the death program. Both there and there the amount of cell mass is 3x10 ¹³. Mysticism?

— The Institute of Oncogynecology and Mammology was founded in 2017. With what results do you celebrate the anniversary year, is there anything you would like to share with our viewers and readers?

— Over these five years, we have managed to do a lot. I will tell you about three important areas that we have managed to implement and that we are developing.

First of all, this is a problem of a combination of cancer and pregnancy. We managed to form a team of different specialists within one institution who are involved in making decisions about the treatment of cancer, the tactics of pregnancy and childbirth, as well as the unconditional prospects for the birth of a healthy child.  I often had to travel around the country during the pre-war period. We have often encountered a situation when a woman was diagnosed with both a tumor process and pregnancy at the same time. We have witnessed how decisions were made in such situations: as a rule, first of all they tried to get rid of pregnancy, which is not very correct. Our experience shows that in the overwhelming number of such situations it is possible to preserve pregnancy and begin treatment of the oncological process.

The second point: there are a lot of young women who, unfortunately, get cancer, and subsequent treatment is associated with the fact that they may lose the possibility of reproduction. Therefore, at this stage we are deciding how to make sure that after recovering from cancer, a young woman can become a mother. This is a very powerful part of cancer rehabilitation. 

The third point: we are trying to slightly change the configuration of the treatment of the oncological process, and this immediately affected the effectiveness of therapy. Understanding of the modern pathogenesis of the malignant process and multi-target drugs reveal the prospect of effective treatment.   

— Thank you very much for the interview. Good luck to you in your big business.

References for additional study of the topic: 

1. Gatenby, R., Gillies, R., and Brown, J. (2010) The evolutionary dynamics of cancer prevention, Nat. Rev. Cancer, 10, 526–527.

2.  Black WC, Welch HG (1993) Advances in diagnostic imaging and overestimations of disease prevalence and the benefits of therapy. N Engl J Med, 328(17), 1237-1243. 

3. Hyuna Sung, Jacques Ferlay, Rebecca L. Siegel et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries, CA: A Cancer Journal for Clinicians, 71 (3), 209-249.

4. Cancer statistics in countries for 2020 according to the World Health Organization: https://gco.iarc.fr

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