Yes, in fact there is a big paradox about the role of inflammation in cancer. It seems that inflammation is deleterious in the early stages of tumor (in carcinogenesis).  However, as the tumor progresses and reaches a state where the immune system is coopted , induction of an inflammatory response in this context is desirable (the goal of most immunotherapy protocols is to induce an inflammatory response, basically).Of course this is just a very simple and generic answer about a very complex subject. I suggest reading these two papers: # 1 J Immunol. 2011 Mar 15;186(6):3462-71. doi: 10.4049/jimmunol. Microenvironment-derived IL-1 and IL-17 interact in the control of lung metastasis. and #2 J Clin Invest. 2013 Nov 1;123(11):4859-74.Interferon-dependent IL-10 production by Tregs limits tumor Th17 inflammation. Just my 2 cents here.

Yes, in fact there is a big paradox about the role of inflammation in cancer. It seems that inflammation is deleterious in the early stages of tumor (in carcinogenesis).  However, as the tumor progresses and reaches a state where the immune system is coopted , induction of an inflammatory response in this context is desirable (the goal of most immunotherapy protocols is to induce an inflammatory response, basically).Of course this is just a very simple and generic answer about a very complex subject. I suggest reading these two papers: # 1 J Immunol. 2011 Mar 15;186(6):3462-71. doi: 10.4049/jimmunol. Microenvironment-derived IL-1 and IL-17 interact in the control of lung metastasis. and #2 J Clin Invest. 2013 Nov 1;123(11):4859-74.Interferon-dependent IL-10 production by Tregs limits tumor Th17 inflammation. Just my 2 cents here.

% Does immune/inflammation support early tumour growth?

Certainly. But it is a balance of selection..

% Are patients immunologically tolerant to their tumours?

NO. But it is compromised.

% Do inflammatory phenomena promote metastatic spread and/or seeding?

Essential. It is a cooperation game between tumor and immune cells.

% How do the murine models - including immune reconstitution models - reflect human disease?

In general schema but not at the gene expression level.

% What are the mistakes and deadends that get repeated with each new generation of researchers?

At the conceptual level, immune/inflammation is the essential component in the dynamics of tumor system. Tumor itself is of dynamic ecology, with immune cells as essential players.

* Does immune/inflammation support early tumour growth? Yes, I believe that the inflammatory response does promote early tumor growth.

* Are patients immunologically tolerant to their tumours? I believe that the immune system if capable of capturing most pre-cancerous cells and clearing them without the host even knowing. However, over time this selective pressure leads to "natural selection" of the most immune evasive tumor cells progressing to the next stage.

* Do inflammatory phenomena promote metastatic spread and/or seeding? I do believe that tumor cells secrete factors that promote the upregulation of chemokines at sites of metastasis.

* How do the murine models - including immune reconstitution models - reflect human disease? I think murine models hold alot of potential, if used correctly. I believe each murine model can be used to study and possibly translate knowledge with in a very narrow scope. Finding the right model for a specific question is important.

* What are the mistakes and dead ends that get repeated with each new generation of researchers? I am too early in my career to answer this.

Hi Grant, Great question which I will follow with interest.

Activation of Nox increases steady-state ROS generation, a beneficial condition for tumor development. This latter phenomenon stimulates glycolysis for ATP production without any contribution of the mitochondrion in condition of tumor cells (the tumor cell takes its source of energy from the fermentation, the mitochondria play a major role in apoptosis). In addition increased ROS production drives the tumor phenotype.

Interesting questions but hard to answer accurately. I think that we have not yet sufficient knowledge of the molecular basis of chronic inflammation, because it is on the molecular mechanisms of the chronic inflammation that we must focus on. We know what happens but not how it happens. It is only a phenomenological description. I would analyze the phenomenon in cellular terms, because we speak of alterations of cell types. Evidently there is an initial insult (an alteration of circadian mechanisms?), which induces some cell types to develop pro-inflammatory messages (for instance through the information system of cytokines) involving different cell types and even far away. The types of cells able to receive these messages carry information through interior signaling pathways. Regardless of the changes that this information may result in these pathways, the purpose is unique, that is, to determine specific changes in gene expression. What we generally see in the literature, is an approach heavily functional, from which one can understand the functioning of the various molecular species, but not of the molecular mechanisms on which they rest. This observation is not farfetched, because in the last decade we have seen that the world of proteins is not just populated by globular proteins (e.g. Hemoglobin, enzymes), but there are also the intrinsically disordered proteins (IDP). They represent another side of the protein world, with properties of its own. These proteins do not have a defined structural organization (i.e. fixed in time), but are extremely flexible and mobile and organized into conformational ensembles often very different from each other that interconvert continuously. The closest representation of their physical reality, is that these ensembles contain chaotic populations of conformers, not always equal to each other, but more or less quite similar to the famous random coil described in textbooks of biochemistry with the difference that IDPs are not very soluble in water and sometimes collapse into globules (other than that of the classical globular protein). Many biophysical techniques have difficulties to characterize such flexible structures, because they form very heterogeneous populations of molecules and the properties we measure are only statistical averages. On the other hand, they represent more than 50% of the entire human proteome, they control and modulate all the most important biological events, often they have the ability to interact with more than one hundred different molecular partners in different cell districts (e.g. Sirtuin 1). Moreover, they are regulated by post-translational modifications which give them great functional diversification (HUB proteins) by altering the type of population of the ensembles. Finally, they interact differently from the classic binding, because they use their extreme structural flexibility for fluctuating links. The knowledge of their molecular and physical properties, as well as of thermodynamics, which regulates the strength of the bonding-interaction or the stability of the ensembles (inter-conversion) are still little known, if not unknown. We have essentially a functional working knowledge of them but just now we are beginning to understand the behavior in solution of model systems that can represent them. What is certain is that their physical properties are also at the basis of the so-called amyloid aggregation phenomena, which are reported as common to many diseases of the modern man, from degenerative ones up to diabetes (I and II) and cancer. Until we do not understand the multiple structural behavior of these proteins in relation to the environmental context in which they operate, it will be very difficult for us to fully understand the molecular mechanisms of inflammation and cancer, as well as other diseases resulting from chronic inflammation. While the information is managed by the membrane and the genome suggests the way through which can be solved a biological problem, these proteins are the main actors which drive metabolism and function of cells. If we do not fill this gap through multidisciplinary study groups, we run the risk of having a sterile knowledge leopard spots. Without knowing the molecular mechanisms is hard to design good drugs with fewer side effects.

Let me advise you of our article, which sanctified these questions - "Pathogenesis of Cancer: Cancer Reparative Trap" Online http://www.scirp.org/journal/JCT/ (DOI: 10.4236 / jct.2015.65043). This article is not PubMed.

However, the study of genes bear no use in studying the problem affected you.