Keywords

Introduction

The present article aims at further investigating the question whether normative notions, i.e., normative structures (morphology and topology), action norms (inclusively the hallmarks of cancer, i.e., sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, reprogramming of energy metabolism, evading immune destruction as well as genome instability and tumor-associated inflammation), and decision maxims (hubs and nodes), as purposive action profiles of a tumor compartment are arbitrarily selected for better comprehension of the validity and denotation of tumor systems objects, i.e., pathways, cells, gene expression profiles, transcription factors, cell interactions, etc. The second question is whether normative notions become—to the contrary—physically rationalized, functionally established, and even protected because of their fail-safe maintenance properties [1–4]. Thus, normative notions would be also constitutive for the ‘metabolism’ of evolution in tumors.

Considering the multifold possibilities (redundancy) of how cells or cell communities constitute rationalizations for the fail-safe function as well as the frequent context-dependent multifunctionality of tumor systems objects—exemplified by NF-κB and p53—, we may become confused about the ‘true’ assessment of the communicative expression of tumor systems objects or their denotation within established rationalization processes [5, 6].

In contrast to the assumption of an retrospectively ensued contentual loading of the term ‘rationalization’, we would like to show that a tight conceptual and scientifically verifiable coherence has existed between the two concepts ‘rationalization’ and ‘normative notions’ from the very beginning, even though only implied as ‘tumor-associated angiogenesis’ or ‘tumor-associated inflammation’ (the hallmarks of cancer), etc. Consecutively, the evolution-historic way, i.e., how rationalizations are constituted in molecular detail, reaches therapeutic relevance. Likewise, the pure molecular identity of a potential therapeutic target dwindles in importance because its situative communicative expression has to be added for guiding therapeutic decisions and personalizing systemic tumor therapies [7].

The evolutionary-driven constitution of the normative substance of rationalization processes as well as the cellular recourse on distinct and—within an evolutionary context—restricted tools of rationalizations for the fail-safe maintaining of normative notions draws on communicative competition, even if ‘corrupt’ rationalizations develop, as in the case of tumors. On the basis of non-random multifacetedly acquired molecular-genetic aberrations, tumors represent a very good example and model to investigate the diversity of ‘individual’ rationalizations, particularly in tumor entities such as acute leukemia [8].

Method

The inseparable relation between rationalization processes, which are supposed to organize and to ensure the physical expansion and maintenance of normative notions, and normative notions may be shown at three observation levels, (1) genetic code—rationalization—normative notion, (2) biomodulatory therapies—rationalizations—normative notion, and (3) communication-derived pathophysiology of rationalizations of normative notions (Fig. 10.1).

Fig. 10.1
figure 1

Features of tumor-immanent normative notions

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  1. 1.

    For many reasons (i.e., context-dependent validity and denotation of tumor systems objects; convergent evolution, that means multiple rationalizations for one dominant normative notion; and robustness of rationalizations), normative notions do not constitute a posteriori classifying phrases or dummies that hide a broad variety of arbitrary tumor-associated phenomena. On the contrary, normative notions are a source of the ‘metabolism’ of evolution, supplied by the substance of all rationalization processes mediating normative structures, action norms, and decision maxims.

  2. 2.

    Furthermore, the catalytic role of normative notions in composing rationalization processes of the ‘metabolism’ of evolution and rationalization can be systematically highlighted from historic aspects and from a therapeutic point of view.

  3. 3.

    Finally, the origin of rationalization processes deriving from normative notions explains the context-disrupting explosive nature of a concrete ‘utopia’ realized in a normative notion. This condition turns in a scientifically accessible way on the general distortion of rationalization processes in tumors (inconsistencies, deformations, Achilles’ heels) as well as on their radical substance (corrupt rationalizations), which is best outlined by its observable robustness towards (therapeutic) disturbances from outside.

Results and Discussion

Ad 1) Because of their abstract universality, the normative structures, action norms, and decision maxims of tumors require concretization in each separate case, i.e., description of cellular, biochemical, and systems levels and specification of the stage-dependent physical constitution in an evolutionary context.

Thereby, multifaceted acquired digitalized structures, which are anchored in the genetic code and constitute the frame for distinct normative notions via rationalizations, may attain multifaceted starting points to establish unique normative notions[8]: Convergent evolution [9] may be even highlighted in acute leukemia. The already anamnestically obvious, rapid onset of leukemia-associated symptoms——induced by bone marrow insufficiency—is marked by a very broad variety of single or cumulatively acquired molecular-genetic aberrations. As the different types of acute leukemia share a dominant normative notion, rapidly displacing growth, the notion achieves facticity: Rapid leukemia evolution may be realized by the ‘metabolism’ of evolution via multifaceted and differentially established rationalizations. Kvinlaug et al. causatively described the occurrence of ‘disparate oncogenes’ [8]: Differential functions may be attributed to oncogenes dependent on the leukemia-specific concert of aberrations. Beyond the context-dependent acquisition of differential functions of oncogenes or driver mutations, their predictive value may change dependent on the additional clinical background, which again is founded in the concert of molecular-genetic aberrations [10].

The redemption of a unique normative notion from scientifically and profoundly assessed multifaceted genetic starting points including frequently occurring recurrent genetic aberrations outlines the varying validity and denotation of single aberrations against the background of an evolutionary specified genetic context. Multifaceted aberrant genomes constitute a broad diversity of rationalizations for maintaining the dominant normative notion, according to which a whole group of diseases, namely ‘acute’ leukemia, is clinically classified [11].

Now, differential rationalizations constituting a unique phenotype achieve an equivalent classifying substance and could present as decisive guides for ‘rationalization-targeted’ (personalized) therapies in future. Furthermore, tumor-specific and stage-specific rationalizations with entirely unforeseen validity and denotation of underlying oncogene-addicted structures, driver mutations or generally therapeutic targets are the major reason for the limited practice of so-called targeted therapies in unknown and novel evolutionary systems stages [8, 12]. The frequently weak efficacy of classic targeted therapies empirically underlines the heterogeneity of rationalizations, particularly in the molecular-genetically highly heterogeneous types of acute leukemia. The novel classifying principle, i.e., the systematic comprehension of rationalizations at genetic and protein level etc., will lead to evolution-adjusted tumor pathophysiology (Table 10.1).

Table 10.1 Top-down and bottom-up strategies use quite different targets for redirecting and modulating the tumor’s normativity
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Accordingly, normative notions subsume more subjacent differences, such as multifaceted rationalization processes. The function of a communicatively determined compromise, which normative notions accomplish in the course of the differentiation and expansion of rationalization processes, may not explain their occurrence as a specified rationalization concept in tumors. Experimental data on context-dependent functionality—particularly of transcription factors—and clinical data obtained through biomodulatory therapy approaches show that modified evolutionary contexts only communicatively address the aspects that are implicitly inscribed in rationalization processes, namely normative structures, action norms, and decision maxims [13–16].

Correspondingly, cells refer back to repair mechanisms or mobilize alternative rationalization processes from an accessible tool to maintain normative notions (robustness) if normative structures are exposed to unexpected perturbations [17]. Hence, detection of violated normative notions and respective repair mechanisms have the function of uncovering communicative rules as well as inconsistencies, deformations, and Achilles’ heels of expanding rationalizations during tumor evolution.

From the capacity to focus on the protection of normative notions, the importance may be delineated, which robustness [18–20] has achieved for the fail-safe function of rationalization processes. The stronger robustness permeates the whole system of cellular rationalizations, the more frequent its interference with the vertical relation between single cells. Just in the case of tumor development, collisions accumulate (implementation of molecular-genetic abnormalities, ‘stress’), necessitating intercellular communicative assessment between competitive rationalization claims according to communication-derived rules. In such decisive ‘hard cases’, decisions are only possible by a recourse on the violation of a valid and priority-claiming normative notion (which could also be therapeutically supported for prevention). In the case of tumor initiation, an overthrown normative notion may be uncovered within a ‘physiologic’ cell compartment accompanied with a corrupt rationalization.

The ‘hard case’ may be simulated by the experimental implementation of non-normative boundary conditions, e.g., cellular ‘stress’ in prostate cancer cell lines, which alters the denotation of the androgen receptor. The receptor then physically participates in establishing a recurrent chromosomal translocation, TMPRSS2:ERG and TMPRSS2:ETV1 (‘corrupt’ rationalization following androgen treatment and genotoxic stress): A distinct, externally implemented rationalization leads to specific chromosomal aberrations, indicating that rationalizations are principally in bidirectional communicative exchange with the digitalized system of the genome [21]. Rationalizations are—on the basis of normative notions and the ‘metabolism’ of evolution—the digitalized counterpart of the genetic code and may contribute to decipher the genome-centric ‘world’.

After having systematically observed tumor development on the basis of increasing lifetime expectation for many decades and the introduction of steeply growing numbers of technologies and (biomodulatory) therapies for studying cancer, we now realize the benchmarks of tumor development: Normative notions, which outreach the traditionally noted hallmarks of cancer by far, are the framework by which the universal substance of the ‘metabolism’ of evolution is imported into novel rationalization processes.

The idea of normative notions is the conceptual hinge that merges the ‘metabolism’ of evolution in every cellular structure and function with respective physically comprehensive and directly scientifically accessible rationalization processes. This mergence occurs in such a way that a distinct cellular organization originates from the interplay at a circumscriptive and compliantly evolutionary stage (cellular ‘living’ world), which is based on the robustness of different rationalization processes. As the ‘metabolism’ of evolution may be redeemed in specified rationalizations, the expansion of rationalizations shows a Janus face, which is simultaneously directed at the ‘metabolism’ of evolution and at the communication-derived norms (rules) for constituting rationalizations [22].

Ad 2) To date, normative structures (for instance, molecular-genetic aberrations in tumor and stroma cells) and action norms, such as the hallmarks of cancer, constitute a realistic utopia insofar as they do not make us believe any longer that tumor cells are a contextless driving force during their evolution [23]. But simultaneously, we only hesitantly dare to attribute concrete validity and denotation to individual and multifacetedly differentiated tumor cell components. Anyhow, normative structures, i.e., angiogenesis, inflammation etc., are acknowledged ‘per se’ as indispensable for tumor development [3, 24].

The following tasks are crucial for extending the instruments for designing personalized therapy approaches: to estimate the situate validity and denotation of normative notions in the tumor compartment, to get information on the communicatively guided competition of various normative structures in the tumor, to identify the particular cellular driving sources, and to analyze how normative notions are physically and functionally rationalized in a distinct evolutionary context. This way, rationalization processes may be categorized beyond the traditional classifying principles, i.e., disease traits and histopathology, which redraws the attention to tumor pathophysiology. Tumor pathophysiology needs to be reconsidered and may have to be re-established as evolution-adjusted, clinical, and particularly personalized tumor pathophysiology [25].

Biomodulatory therapies are directed towards robustness of rationalization processes by redeeming novel validity and denotations of systems objects in the context of a tumor’s evolutionary confined ‘living’ world, i.e., its holistic communicative world [26]. Vice versa, biomodulatory therapies may give decisive clues how normative notions are rationalized in a distinct evolutionary context, as exemplified by modularly targeting tumor-associated inflammation [27].

The proper functioning of biomodulatory therapies in metastatic cancer underlines that regulatory active, multi-targeted therapy approaches, which primarily focus on non-oncogene addicted structures and functions, may exhaust the communicative capacity of a tumor’s ‘living’ world [14, 16]. Thereby, normative notions, which are basically supported by ‘oncogene’-addicted structures and functions become redirected and placed. In acute myelocytic leukemia, first biomodulatory therapy approaches with a nuclear receptor agonist, i.e., all-trans-retinoic acid, have shown significantly improved overall survival rates in cytogenetically defined subgroups, besides the classic application in promyelocytic leukemia [28]. All these therapy-derived observations indicate that the normative notions of tumors are therapeutically placeable via communication-derived rules grounded in a tumor’s ‘living’ world: Normative notions, which are frequently accessible as disease traits—as in the case of ‘acute’ leukemia—, are available for therapeutic modification by implementing rationalization-specific and non-normative boundary conditions, i.e., biomodulatory therapies (transcriptional modulators, metronomic low-dose chemotherapy, etc.) [14]. Because of the established and therapeutically relevant altered communicative prepositions during biomodulation, the term ‘oncogene’ must be relativized, because only the therapy-naive tumor-associated communicative context refers to the denotation as ‘oncogene’, which again may be specified in the context of multiple additional molecular-genetic aberrations (‘disparate’ oncogenes).

Ad 3) Reductionist-oriented targeted therapies provoke tension in the current therapeutic scene: Apart from some exceptions, therapeutic results obtained by reductionist approaches disclose more and more frequently a gap between the perceived (preclinical) norms and expectations—stated by reductionist theories on oncogene-addicted targets or driver mutations—and current, rarely sweeping therapy results, which are often taken from very small patient populations [29–33]. Reductionist knowledge draws on uniquely defined communicative circumstances, which are self-evidently assigned to novel evolutionary confined systems stages, as is the case in the therapy of acute leukemia. The strategy to target oncogene-addicted structures and driver mutations is commonly linked to the perception of personalized tumor therapy.

The interruption of a rationalization process at any optional biochemical level (traditional targeted therapy), necessitates the tumor’s living world to react with alternative rationalizations. In the situative communicative expression of a target lies the rub, as seemingly unexpected ‘effects’ and ‘side effects’ may occur. Reproducibility of side effects, and side effects dependent on the treated histological tumor type, as outlined for sorafenib, a tyrosine kinase inhibitor, and its differential activity in acute myelocytic leukemia, renal clear cell carcinoma and hepatocellular carcinoma [12, 34, 35], again underline that rationalizations are highly specific.

However, the novel practice of creating applied systems biological therapy approaches brings on a completely new problem: Biomodulatory therapies also claim universal validity. They aim at targeting the weak points in the execution of rationalization processes or at redirecting a tumor’s normative notions to achieve the attenuation of tumor growth. Basis for the therapy design is the analytic and empiric comprehension of tumor-associated rationalizations, which equally encompass both the digitalized genome-centric ‘world’ and the modularly structured cellular ‘world’ [26, 27, 36, 37]: The tumor’s rationalizations represent an independent counterpart to the tumor’s genome with its acquired aberrations.

For establishing evolution-adjusted tumor pathophysiology, each norm, the substance of a systems object (i.e., its background knowledge), is scrutinized with regard to its communicative context, which attributes notable validity and denotation to systems objects in a distinct evolutionary systems stage [27]. Does a novel evolutionary context attribute identical validity and denotation to a systems object as uncovered for the respective systems object in the evolutionary context studied originally? Is the respective systems object part of a novel rationalization process, constituting a distinct normative notion [12]? Multifold experimental data highlight NF-κB as a colorful ‘matchmaker’, when inflammation meets cancer [38].

Normative notions may be studied starting with the comprehension of the tool of possible rationalization processes (redundancy, robustness), for example, by describing which cell compartments primarily contribute to tumor-associated inflammation, angiogenesis, immune response etc., and which communication lines are activated with regard to communicative expression. Furthermore, normative notions may be studied by recording the secretome of cellular compartments of the tumor in patient serum, which is indicative for the presence of distinct normative notions, or by monitoring changes derived from molecular imaging, which may give indications for the therapeutic redirection of normative notions [27, 39–41].

Conclusion

Normative notions are pragmatically and discursively selected. The study of normative notions (Fig. 10.1) and respective rationalizations in tumor systems including their systematic classification needs to be institutionalized to constitute evolution-adjusted tumor pathophysiology as the novel language of tumor biology and to facilitate novel biomodulatory therapy approaches, i.e., cellular therapies in situ (Table 10.2).

Table 10.2 Rationalizations of tumor-immanent normative notions represent the non-genomic counterpart of the tumor genome and have to be systematized in the same way as genomic structures and functions
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