Origin of Cancer: Cell work is the Key to Understanding Cancer Initiation and Progression

The cell is the smallest unit of life. It is a structure that maintains order through self-organization, characterized by a high level of dynamism, which in turn is characterized by work. For this work to take place, a continuous high flow of energy is necessary. However, a focused view of the physical relationship between energy and work is inadequate for describing complex biological/medical mechanisms or systems. In this review, we try to make a connection between the fundamental laws of physics and the mechanisms and functions of biology, which are characterized by self-organization. Many different physical work processes (work) in human cells are called cell work and can be grouped into five forms: synthetic, mechanical, electrical, concentration, and heat generation cell work. In addition to the flow of energy, these cell functions are based on fundamental processes of self-organization that we summarize with the term Entirety of molecular interaction (EoMI). This illustrates that cell work is caused by numerous molecular reactions, flow equilibrium, and mechanisms. Their number and interactions are so complex that they elude our perception in their entirety. To be able to describe cell functions in a biological/medical context, the parameters influencing cell work should be summarized in overarching influencing variables. These are “biological” energy, information, matter, and cell mechanics (EMIM). This makes it possible to describe and characterize the cell work involved in cell systems (e.g., respiratory chain, signal transmission, cell structure, or inheritance processes) and to demonstrate changes. If cell work and the different influencing parameters (EMIM influencing variables) are taken as the central property of the cell, specific gene mutations cannot be regarded as the sole cause for the initiation and progression of cancer. This reductionistic monocausal view does not do justice to the dynamic and highly complex system of a cell. Therefore, we postulate that each of the EMIM influencing variables described above is capable of changing the cell work and thus the order of a cell in such a way that it can develop into a cancer cell.

concentration in the cell. Some cell mechanisms are disturbed in such a way that the result is increasing disorganisation in the cell and malignant transformation 1011 . According to Warburg, tumour cells always engage in increased glycolysis. This "fermentation" of glucose in the presence of physiological oxygen concentrations is called the Warburg effect or "aerobic glycolysis".

Pro:
The theory is supported by the fact that the vast majority, if not all tumour cells have an altered energy metabolism.

Contra:
a. It has not been proven whether the mechanism described by Warburg underlies the development of all tumours 12 . In fact, it is considered in the textbooks to be a result of the hypoxia or oligemia present in the tumour tissue. b. Why do patients with a congenital disorder of mitochondrial function not have a higher risk of cancer? 13 ? The Warburg hypothesis postulates that a disturbed energy balance causes the development of tumours. As a result, patients with mitochondriopathies should have an increased risk of tumours. However, this is not the case. c. Doesn't aerobic glycolysis represent a general physiological reaction of metabolism in proliferating cells rather than a tumour-specific mechanism? References to this differentiated view of the Warburg effect are provided by the publication of Vander Heiden 14 . d. Not all tumour cells show a disorder of mitochondria or oxidative phosphorylation. 15

Disturbed microenvironment
Another theory on cancer initiation and tumour progression is the development of tumours on the basis of a disturbed cell milieu or environment 1617 . The assumption here is that through the change in the cell environment, for example through inflammation, hypoxia, oligemia, toxins, etc., the cells increasingly change in terms of adaptation, so that ultimately a tumour cell develops. highly malignant breast cancer cell led to a loss of tumour malignancy and that tumour-specific pathomechanisms were also attenuated 2526 . c. Is the mutation a consequence of the "unfavourable" environment or is the altered milieu alone the cause of tumour initiation? This question has to date remained unanswered.

TOFT theory
The Tissue Organization Field Theory (TOFT-theory) 2728 assumes that cancer cells arise from a loss of interaction of the cells with their surrounding tissue. This interaction takes place through intercellular "chemical exchange", mechanical forces and bioelectrical interactions. Since these processes play an important role in embryogenesis, the TOFT theory is also called development gone awry. The theory assumes that carcinogenesis is characterised by disturbed tissue organisation and high cell proliferation. Three conclusions arise from the TOFT theory 29 : 1. Mutations are not necessary for the development of cancer. 2. Tumours also develop without tissue/cells having previously come into contact with carcinogens. 3. Genetic instability is a byproduct of carcinogenesis. Pro: In several experiments it could be shown that after the implantation of tumour cells into a normal healthy stroma tissue, these functioned like normal cells. 3031  Contra: If the transfer of functionally normal mitochondria leads to the loss of malignancy of a tumour cell, 34 the TOFT theory cannot explain this phenomenon, as it considers the loss of cell/cell and cell/extracellular matrix contacts as the cause.

Speciation theory
The theory is that the first step in the development of cancer is characterised by numerical and/or structural changes in the chromosomes. Depending on the type of change, they show a massive loss or gain of DNA/genes, which leads to an imbalance. Eventually, a cancer cell can develop from this.
Pro: Many solid tumours are aneuploid. In addition, precancerous lesions (dysplasias) or inflammatory tissue are characterised by chromosomal changes and instability 35363738 .

Contra:
a. Aneuploidy and chromosomal aberrations are irreversible changes which, according to this theory, are responsible for the initiation and progression of tumours. But how does the theory then, explain the loss of malignancy in tumour cells when healthy mitochondria have been injected into them? 37 b. Not every tumour shows chromosomal changes 3940 . c. Constitutional aneuploidies can be identified in the brain 41 . Based on the aneuploidy hypothesis, it could be concluded that these patients would have an increased risk of developing a brain tumour. However, this is not the case. d. Patients with constitutional trisomy 21 show an increased incidence of leukaemia, but they have a 50% lower risk of developing solid tumours 4243 . 34 Crosstalk from non-cancerous mitochondria can inhibit tumour properties of metastatic cells by suppressing oncogenic pathways. PLoS