In the last several decades, literature has got flooded with publications addressing the significance of microenvironment [1] in the evolution and perpetuation of neoplastic transformation [2]. Cells comprising the microenvironment ranging from fibroblasts to immune cells and their derived growth and immunomodulatory factors have been elucidated to a significant degree [3]. Thalidomide, the first generation IMiD [4] was perhaps the starting point in addressing the growth and proliferation signals originating in microenvironment of multiple myeloma [5]. Such inhibition, opened a new chapter in treatment of multiple myeloma many years ago. Programmed Death-1 antagonists [6] unleashing the tumor destructive capability of immune cells residing in the microenvironment, present another example in the fairly recent cancer therapeutic literature in this regard. Lack of universal success by using these agents in different types of neoplastic disorders, denotes a much deeper level of complexity in the interaction of microenvironment and cancer [7], that has yet not been tapped on. As such, one might reasonably conclude that there is no black and white relationship between microenvironment and cancer, and rather there are different grades of grey. To address these variations and uncertainties, one needs to refer to the most fundamental law that determines the fine tuning and creation of living organism, namely the second law of thermodynamics [8]. The deep dissection of the interplay of the second law of thermodynamics and living cell and its breakdown [9], would enable us to come up with a model that could potentially describe these variations and generate a blueprint to address different dominant scenarios in different malignancies.

Microenvironment, could perhaps be best defined as a barrier between the pro-entropy environment and the living cell [10]. Some thirty-eight hundred million years ago, when the first prokaryote was born in the boiling and salty water of the primordial ocean [11], the only barrier between the genome and the pro-entropy environment was the cell membrane.

With the birth of eukaryotes [12] and later on multi-cellular organisms [13], more sophisticated barriers, such as nuclear membrane [14] and transcellular pumps and transmembrane receptors came into existence [15].

These barriers, pumps and receptors [16] acted as guardians of the cellular genome, helped with extrusion of noxious agents and transfer of life sustaining elements to the living cell.

The history of evolution of life on this planet could be best defined as a constant tug of war between the pro-entropy environment [17] and universe on one hand and the anti-entropy living cells [18], which have become able to secure the lowest amount of cellular networks entropy [19] and maximum free energy [20], on the other hand. The major means of such achievement, has been the buildup of more sophisticated barriers, as well as growth and survival loops.

Along the same line, microenvironment has come into existence to generate a safe and protective bed for living cells and tissues. However, numerous pro-entropy forces and elements are constantly attacking the cell and the microenvironment.

Consequently, both the cell and the microenvironment should be able to constantly antagonize such pro-entropy elements and repair their ensuing damage [21]. Inflammation and inflammatory signals [22] could be considered the most immediate and lethal agents, threating the integrity of the genome. Radiation and environmental toxins and chemicals are constantly damaging both the cell and the microenvironment. Simultaneously, passage of time along the thermodynamic arrow would independently lead to increase in entropy. The living organism is loaded with protective mechanisms and sensors of damage at all levels, ranging from genome to epigenome and micro-RNA network all the way to membrane and microenvironment [23].

As one example, mid-life examination of cells of different human tissues has revealed numerous mutations aiming at pro-inflammatory damaging signals [24]. Such mutations, which have come into existence to protect the cell, would prove carcinogenic during the latter years of human life. Telomeres would also alert the cell [25], through their shortening along the axis of time following numerous replications and activate apoptosis before catastrophic mutations exert their malignant transformation property.

 The response of the non-cellular compartment of microenvironment to the pro-entropy and damaging environmental agents [26], is through their physical modifications, such as stiffening and architectural distortions [27]. Clearly such physical distortions, which translate into less freedom of motion and plasticity and hence increased entropy would diffuse into the surrounding cells [28].

Consequently, the affected cells' genetic programming get affected at numerous levels, including genome, epigenome, micro-RNA and

protein-protein interactions with the end result of higher cellular network entropy (Figure 1). The answer to the big question of where neoplastic transformation starts [31], has to do with speed and pace of damage of microenvironment and surrounding cells, as well as their speed of recovery and the built-in interdependency which is a function of parallel evolution of these compartments. As such, all possibilities are viable [32]. Consequently, the damaged microenvironment with higher entropy could lead to increase in cellular network entropy of its comprising cells and adjacent cells outside the microenvironment and generate a reverberating vicious cycle.

As one example, in glioblastoma multiform alternate splicing of EFEMP1 RNA [33], would inhibit the formation of ETSP, EFEMP1 tumor suppressor and promote the formation of the oncogenic version of EFEMP1, with its downstream growth and promotion pathway factors and its associated MMP (matrix metallo protease) [34], which would spill into its adjacent microenvironment. EFEMP1, would lead to generation of disulfide bonds of certain matrix proteins, such as fibulins [35]. This would lead to their stiffness and lack of freedom of motion, plasticity and remodeling. This is the proto-type example of high entropy microenvironment.

MMPs, through digestion of matrix proteins would open the way for metastatic spread of malignant cells and for the promotion of mutations and increase in chromosomal/genetic instability and intra-tumor heterogeneity [36].

The combination of simultaneous and irreversible damage to microenvironment and cellular compartment is another theoretical and potential possibility [37].

The surprising and dramatic response of multiple myeloma patients to agents that interfere with growth and proliferation pathways originating in microenvironment [38], is highly supportive of the damaged microenvironment, as the central pathology of multiple myeloma. By the same token, lack of response to such agents in patients with carcinoma of lung, is quite supportive of irreversible cellular damage, as the central pathology in such patients [39]. On occasion, synergistic positive response to combination of treatment against microenvironment and malignant cell, such as certain subtypes of non-hodgkin lymphoma, is supportive of dual, irreversible damage to microenvironment and lymphocyte [40].

Deep understanding of the interplay of microenvironment and neoplastic cell and the dominant role played by each, is in need of dissection of the central role played by the second law of thermodynamics, in initiation and evolution of living organism and the evolutionary dynamics of these two compartments [41].

Evolution of microenvironment as a barrier between the pro entropy environment and the living cell [42], as well as a balanced growth and proliferation promoting ground of the cells embedded in it, plays a central role in this regard.

It is only when the entropy of one or both of these two compartments increases inappropriately and irreversibly, that neoplastic transformation arises [43]. Each neoplastic disease has to be dissected accordingly and customized treatment generated for that specific scenario. As such, the enemy, which is the pathologic and irreversible increase in entropy [44], could come into existence in the microenvironment and expand into adjacent cells, vice-a-versa, or a combination of both.

Development of the future generation of cancer therapeutics, necessitates delicate measurement of systems entropy at microenvironment and cellular levels [45].

It is my hope that programmable nano-machines [46] would get programmed toward decreasing systems entropy in a customized fashion and get delivered to the culprit zone to achieve this goal. By that time, chemo, immune, and radiation therapy would join history (Figure 2).