What are the challenges facing cancer therapy base on the dissipative structure theory

Yue Yang,Ning-Ning Liu,Ming-Yu Sun*,Qi Li*

1Department of Oncology,Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine;Shanghai University of Traditional Chinese Medicine,Shanghai,China.2Key Laboratory of Liver and Kidney Diseases,Institute of Liver Diseases,Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine,Shanghai,China.

Background

Cancertherapy is a tough problem.With the development of genomics, proteomics and metabolomics,high-flux moleculardetection and nanomedicine,cancer therapy becomes increasingly diversified and individualized.However,shortcomings in existing theory such as reductionism is apparently and issues such as the relationship between tumor development and tumor microenvironment,immune response mechanisms and tumor interstitial heterogeneity etc.are not thoroughly inquired[1-6].Cancer is still unable to conquer but faces numerous challenges.To this end,theory renovation of cancer therapy is extremely necessary[7-9].The complexity science is a new science with multidisciplinary and frontier of scientific research,which provides fresh air for medical development[10-16].As the main school of complexity science,dissipative structure theory reveals the unity of human body itself and its external factors,generates theoretical basis for medical mode conversion [17-19].To interpretthe occurrence,progression and treatment of cancer from dissipative structure theory,this paper attempts to put forward a hypothesis that the dissipative structure theory can be applied to cancer therapy and can probe into the new direction of it.

Hypotheses sources

Mr.Stephen Hawking predicted that"the 21st century was a century of complexity science".The complexity science,as forefrontof contemporary scientific development, is continuously moving towards unprecedented prosperity[20-23].Dissipative structure theory,as a major genus of complexity science,is a nonlinear and open system away from the equilibrium state.It changes internal parameters of the system by exchanging materials and energy with environment[24-27].Once the threshold is reached,fluctuation mechanism might be triggered and the"critical points"could be crossed to occur non-equilibrium phase transformation.Additionally,chemical oscillation such as self-organization phenomena may result in a great alteration from original chaotic disordered to relatively non-equilibrium state in time,space or function[28-33].In brief, dissipative structure theory considers"non-equilibrium is the source of order"."Non-equilibrium" is neither “unbalanced” nor“balanced”,but a steady state infinitely close to the“critical point”[34-35].Dissipative structure theory resolves contradictions between the second law of thermodynamics and the darwinian theory of evolution,eliminates the gap between inorganic chemical substance and organism,and finds out rules of disorderly and orderly bi-directional transformation[36-41].Its founder,Pregogine,calls it"a new dialogue between man and nature."[42-44].Since current theory can’t give new thought to treatment,why not make some bold attempts to explore it from the emerging dissipative structure theory?

Figure 1 Dissipative structure theory

Hypotheses contents

According to the concept of dissipative structure theory,human body is a typicaldissipative structure.Maintaining dynamic non-equilibrium state can continuelife.Therefore,oncepathogenicfactors disrupt or destroy the relative non-equilibrium even accumulate to a certain threshold,the organism may shift to disorder,resulting in various diseases and even threaten life.The dissipative structure theory has its specific criteria.The degree of non-equilibrium state in dissipative structure can be measured by"entropy"[45-48].As an open system,when exchanged with the external environment,effective substances obtained from theoutsidemakethe energy continuously increase,which input negative entropy flow.On the contrary,ineffective substances released to the outside make the energy decrease,which output positive entropy flow[49-51].Negative entropy is ordered,positive entropy is disordered.Entropy increases is from order to disorder while entropy decrease is from disorder to order [52-55].Rolf Landauer has mentioned that erasure of information is a process of dissipation,from this logic,and the progress that limited positive entropy outputto external is irreversible[56-57].Hence,the metabolic of the organism always makes body in the state of low entropy or negative entropy.As a dissipative structure,the entropy value of the human body is the sum of the entropy produced by life activity and interaction with external environment.Life activity absorbs ordered matterand introduces negative entropy through interacting, outputs positive entropy through metabolizing excessive aging cells and tissues[58-60].Negative entropy flow corrects body positive entropy and guides body tends to be orderly.Always in a state of low entropy or negative entropy keeps the life activities normal operation [61-63] (Figure 1).Applying the dissipative structure theory to cancer therapy is to interpret it in an emerging theory and find newly direction to treatment from non-equilibrium state.

Hypotheses basis

Cell division and chromosome replication are in accordance with the specific rules of the body.Once it broken,chromosome division will be suppressed and cell apoptosis pathway will be blocked.As we all know,cell is the micro-structure of organism.The DNA as transfer of genetic information in cells may be affected by the mutation factor when microscopic order altered,which could induce the gene mismatch,missing,inserting or re-arrangement[64-66].When original DNA sequencing was undermined,newly synthesized DNA structure will change accordingly,and it may be passed down to the generations.Furthermore,this could activate the original oncogene,or inactivate the tumor suppressor gene in original cell,and translate the previously distinct protein or abnormal proliferation of normal proteins[67-68].Besides,changes in the microscopic may cause the deviation between the protein synthesis and the information transmission in cells.Any variation in amino acid arrangement and the spatial configuration of proteins can lead to alteration in protein,enzymes and nucleic acid functions,which is difficult to reverse once it appears.

The cancer itself and the surrounding tissue carry out the switch of matter,energy and information all the time with its host-the human body.After reaching a certain threshold,it will mutate to a new relative non-equilibrium state.Thus,tumor is also a dissipative structure[69-72].It spontaneously forms channels like neovascularization and lymphaticin exchange to obtain more.Based on the characteristics of abnormal proliferation of tumor cells,it is easy to be unbalanced in the process of communicating with the normal cells in surrounding areas.Under the action of blood pressure gradient,tumor cells may be transferred between the vessel wall and lymphatic.Blood friction or viscous force allows metastasis appear complex and unpredictable[73,74].Vascular and lymphatics spread throughout the body and supply nutrients to organs,so tumor cells can migrate with blood and lymphatic fluid to everywhere.If it adhesion and colonization in the target organs,then form the same type of secondary tumor.From dissipative structure theory,this is the probable reason of recurrence and metastasis of cancer.

The change of"entropy"in dissipative structure theory can also explain the occurrence and development of cancer.Organism,as the host of tumor,is the external environment and provides the basis of material and energy for the survival of tumor.Cancer cannot be isolated from the organism.Once carcinogenesis occurs,original cell homeostasis will be ruined by emergence of abnormally proliferative tumor cells.To constructa new dissipative structure,organization will trigger the fluctuation mechanism,initiate the non-linear action and realize the cooperative operation of self-replication,amplification and communication,so that internal entropy of the body system is increasing[75,76].When positive entropy created by tumor is too huge and the negative entropy derived from external hard to counteract;the cancer will develop further and a series of symptoms is appearing step by step[77,78].In other words,when system positive entropy increase,the negative entropy is too little to resist highly positive entropy,may contribute to the development of cancer.

The basic theories in traditional Chinese medicine(TCM)likes “YinYang”and “Tian Ren He Yi”are all come from philosophy theory,which were recorded in the ancient book of Yijing and Zhuangzi(Zhou Danasty of China,1046 B.C.-256 B.C.)[79,80]. “YinYang”theory insists“interdependence or balance between Yin and Yang”.It underlines the opposite and unified relationship.Although Yin and Yang are the two sides of things,they are interdependent with each other;under certain conditions they can realize mutual transformation,which is similar to the dissipative structure transforming chaos to relatively non-equilibrium state through non-equilibrium phase transition. “Tian Ren He Yi” theory emphasizes“heaven and man are mutually responsive”and “the integration of heaven and man”[81].Human is not an isolated person,but a person in nature and in society.Just like the dissipative structure theory mentioned,dissipative structure can change internal parameters of the system by exchanging materials and energy with environment.TCM attachesgreatimportanceto holistic view,not to cure independent disease,but the sick person.TCM,which can effectively improve the quality of life and reduce recurrence and metastasis,is an indispensable and irreplaceable part of cancer therapy.Thus,the hypotheses that exploring cancer therapy with dissipative structure theory provides a theoretical support for the indispensible role of TCM treatment in the comprehensive cancer therapy.

Cancer therapy and its future

As a dissipative structure,cancer sustains a relatively non-equilibrium state in the switch of material,energy and information.Sinceitcannotbe completely separated from the external environment,it cannot ignore the influence of it,which locates us to inquiry the cancer treatment from dissipative structure theory[82,83].The external environment of cancer can be divided into two levels:for one hand,from the microscopic order,cancer composed by tumor cells is a dissipative structure,whose external environment is the human body.Foranotherhand,from the macroscopic order,the human body is a dissipative structure,whose external environment is the natural and social environment.The reason for occurrence and progression of cancer is relatively non-equilibrium disrupted and negative entropy is not enough to correct high positive entropy.If we want to address the issue from source,what we should do is to preserve the stability of relatively non-equilibrium state.Applying dissipative structure theory to comprehend is mainly to enhance negative entropy to resist highly positive entropy.

From microscopic order to maintain the relatively non-equilibrium state

From the point of view of prevention,we should inhibit the mutation of cells and reduce the possibility of abnormal proliferation of tumor cells.However,inhibition of gene mutation is temporarily hard to accomplish in present,or can be a direction of research in the future.How to control the mutated cells?How to delay the progression of disease and prevent the further deterioration?These are the critical problems that require being resolved at present.Gene mutations determined by genetic factors are potentially irreversible;in addition to the rigorous screening of offspring on the basis of the discovery of the previous generation,universal genetic sequencing may supply more information about genetic mutations,which is of certain significance for early warning,regular review,diagnosis and treatment.

From the perspective of treatment, existing treatmentoptions include: surgery,radiotherapy,chemotherapy,targeted therapy,photo thermal therapy,cryoablation,percutaneous radiofrequency ablation,interventional therapy,immunotherapy,endocrine therapy,TCM,acupuncture treatment,the joint comprehensive treatment,etc.All of these is to cut positive entropy of system or import negative entropy from outside to counteract the highly positive entropy[83-85].Thereby,to optimize the cancer treatment and smash the bottleneck,we should break the mindset of thinking,experiment diverse approaches to diminish positive entropy or gain negative entropy.According to assessment of specific situation, refinement of individual classification and reference to different types of tumors,tumor staging,physical conditions,subtype combined clinical and basic experiment should be accurately established.

From macroscopic order to maintain the relatively non-equilibrium state

From physiological considerations,life activities and diet structure,emotional changes and living habits are intimately linked.People in naturaland social

circumstances could maintain their relative on-equilibrium only to find the balance between external factors and themselves[86,87].Taking the influence of emotion for example,long-term mood disorder may lead to neurological,endocrine and immune system disorder.Especially when the immune system is dysfunctional,neither organism can stop normal cells from mutating into cancer cells,nor timely identify and mobilize the whole immune system to kill cancer cells.Adjusting the diet and psychology,regular living habits can decline positive entropy to maintain the relative non-equilibrium.Meanwhile,psychotherapy and social therapy would also assist cancer therapy by increasing negative entropy.People who are good at communication and able to adapt to social life might have a better openness of the emotional system,a stronger participation in the social environment.These people usually acquire greater negative entropy to keep fit[88-91].Cancer therapy ought pursuit “people-oriented”and consider both physiological and psychosocial factors of the patients.Taking pathological into consideration, the maintenance of life activities is intimately associated with water-electrolyte,metabolism and acid-base disturbances, pathogenic microorganisms and infectious diseases.Apart from tumors,for the patient with basic diseases such as hypertension and coronary heart disease,whether the tolerance of cancer therapy or the response to body's consumption will be greatly weakened.Maintaining the whole body basic level in steady state,vigorously treating other basic diseases,and minimizing non-tumor diseases on body consumption may reduce the system positive entropy to achieve the goal of cancer therapy.It is also one of the possible reasons for enhancing immunity,improving the quality of life and prolonging survival period of cancer patients.

Building a new relative non-equilibrium state

Explore assiduously,but we have not yet conquered cancer.Do we have to eradicate the cancer?What shall we do if we can't get rid of it?In the constant groping,we found a new way;that is,survival with tumor,which means stabilize the tumor and prolong the survival period as long as possible to under the premise of maintaining the body's reactivity to tumor.After all,tumor-free status is not always converted to the extension of survival.Blindly pursuit the tumor-free survival and over-treatment cannot benefit all cancer patients.On the contrary,chasing for the statue that survive with the tumor can give both doctors and patients confidence in treatment and improve the quality oflifeto someextent.When relatively non-equilibrium broken,cancer occurs and progresses further.Hence,we may boldly conceive that if we establish a new relatively non-equilibrium state,is it possible to stay in the temporary stability,reduce the hazard of recurrence and metastasis,and improve the quality of life?

In recognition of the established reality of tumor existence,we attempt to set up a steady state for remaining the coexistence of body and tumor by drug and other treatment[92-93].By constructing a new relatively non-equilibrium state to increase negative entropy from the inside,so that the organism can obtain better quality of life and longer overall survival.It is also a point that the dissipative structure theory has told us.

Conclusion

Cancer therapy faces many challenges.From the dissipative structure theory to explore the challenge of cancer therapy,we get plenty of illuminations in the emerging theory.Once positive entropy increases,negative entropy is insufficient;negative entropy is difficult to resist highly positive entropy;it may induce the occurrence and progression of cancer.Discussing the influence of dissipative structure theory on normal organism,cancer and cancer therapy,broaden horizons to cope with problem.Regrettably,dissipative structure theory as a new theoretical system has not been widely accepted and applied.The discussion on treatment of cancer is limited,and how it be transformed into specific methods or used in clinic is still a mystery.But we can still boldly assume that dissipative structure theory can find a new direction for cancer therapy.Be optimistic,admit unknown,abandon linear stereotype thinking and give adequate play to initiative and creativity,we would apply dissipative structure theory more flexibly in the future to lead us infinitely approach to the destination of cure cancer.

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