The simple answer is: none, or all! Cancer is not the ends result of a pre-programmed progressive development of consecutive signalling pathways, or individual signalling events, it is the emergent property of multiple subtle changes in "normal" signalling.

The simple answer is: none, or all! Cancer is not the ends result of a pre-programmed progressive development of consecutive signalling pathways, or individual signalling events, it is the emergent property of multiple subtle changes in "normal" signalling.

Agree with Christer. In Patients, as physicians, we would like to have such markers, but thatis, at the moment impossible. Also because of a simple "mathematical" principle: an invert relation between specificity and sensibility. If you increase the sensibility for a method of detection, you decrease your specificity. You always have to put in balance the two. Like for "uncertainty principle" of Heisenberg in physics.

Best regards

Didier

Although i agree with the other answers in principle, actually there could be something: that is the epithelial-mesenchimal transition that is normally supposed to take place for invasion and metastasis of the cancer cells. Kind regards.

Full agreement with Christer and Didier.

I support the Engin's concept of Invasion and Metastasis.

I would like to add that, Loss of adhesion Eg. Wnt Signalling could be an advancing signalling event, because these signalling makes the cancer in more advanced state such as Loss of cohesion, motility, and invasion in to another area. Hence the molecules that are involved in loss of adhesion, invasion and metastasis can be categorized as advanced signalling molecules in Cancer.

Like Christer and Didier, there is no real sequence of cancer development. I highly recommend you read Hanahan and Weinberg's Hallmarks of Cancer paper itself here: (Maybe you have already read this)

http://www.cell.com/abstract/S0092-8674(11)00127-9#MainText

This paper is an update to their first version of "Hallmarks of Cancer". You will see by just comparing the first version and the latest version, they themselves had to change many of their stricter divisions in their first paper.

Loss of adhesion, invasion and metastases if often considered a later stage. However, this is not strictly so. Circulating tumor cells can arise very early.... some of these must have come thru metastases.

Finally, cancer is a pure statistical/stochastic/process of chance. In this scenario, there is no real STRICT first.

The current views expressed about cancer in relation to advanced signalling are helpful and true, however, the known and still being known signalling work uniformly, and of course, abnormally, to gain an advantage over the normal cell's survival, growth, etc.

When a person is resting, normal cells would get barely enough blood to survive because their capillary gates (e.g. sphincters, pericytes, etc.) are not fully opened for unknown reasons (this is my own logical deduction from observations of children developments). Whereas, advanced stage cancer cells get all the blood that they want thru their own capillaries. This is a thought that you should look at their blood flow images when they are resting or sleeping. I could imagine that their blood flow patterns will show greater differences if you put patients on treadmills. But they won't last long as their cancer cells will grow even faster.

Arguably, the critical hallmark of advanced cancer is that the metastatic cells are able to settle into tissue in which they would not normally reside; the angiogenic properties that allow these cells to proliferate in these sites are subsidiary.

I agree with Christer but still, there might be changes that more typically occur in advanced cancers. Yet I am not sure whether there is much information on such events. The often aggressive last stage of cancers might be determined more by the reaction of the host than by signaling in the tumor cells.

Pao Yen, In case of malignancies / cancer events, the mutant cells deposit a signals of blood vessel / capillary stimulants such as VEGF (Vascular Endothelial Growth Factor). These are considered to be a angiogenic molecules., these molecules are considered to gain the vascular supply to the new growth of tissue i.e., cancerous tissue.

Simple answer: Look at what happens in the case of resistance. I would argue that advanced cases and resistant cases have much in common. If you are curious about specific genes probe the web, there are a lot of databases with info depending on your cancer model. Complicated answer: Even within a single tumor there are seperate populations of cells that may behave very differently, there will not be a single answer for cancer altogether or a single cancer type. However, personalized medicine (albeit more expensive) may be the answer for a single patient. Good luck!

I agree with all arguments above... if you ask about the cancer signalling in advanced cancer, the answer basically would be: "we still dont know"! Cancer cells are very smart and the signalling pathways are like a puzzle seems never ends BUT can be controlled. now there is much more besides the signalling it self which paly a major role in determinning and defining cancer to be staged as an advanced. one is the tumor microenvironment and the other the immune system. recently reports indicated a significant role if T regulatory cells in avoiding immune survillance for tumor cells helping them to escape and the rest of the hallmarks of cancer then took place. thus contributing to the progression of cancer to advance stage. reports also showed decrease survival rate in different tumors that the microenvironment was predominant by T reg cells.

I essentially agree with the various answers given. However, I do not think that it is possible to completely generalize. E.g. in the colorectal anatomical sequence there is an early and a late pattern: polyp to cancer, that is also present in part at least in the biological make up from early methylation to late P53.

I agree with the various explanations given. However, Mario Dicato pointed out correctly of the sequence of event from polyp to cancer. As he mentioned it is not possible to generalize.

After agreeing with everthing above I have read your question again. I am not sure we are answering it properly. At a molecular level many mutational events may occur within a tumour cell population, indeed the tumour cell population may be very hetrogenous in the actual and combination of mutations within each tumor cell. What happens is a kind of somatic mutational evolutionary selection of cells that exploit the environment (the human body) for their own replication. At a clinical level generally the first step is a lossening of the controls of cellular replication; this does not mean that in some cells other "next stage" clinical signal mutations have not already occured. This can result is a larger population of cells of a particular type a dysplasia or a wart if the sole mutations are lossening of replication. However, angiogenic factor mutations may make this a very large lession; or if cell adhesion and chemotectic mutation have occurred in combination a lession that is a true cancer and invades other tissue layers. However, the advanced Signalling I believe you are asking are mutations that allow tumour cells to grow in distant and different tissues to which they arose. I think you are asking what mutations signal metastasis. This is the current target in biomarker research. What we know is that tumour cells can be shed into and isolated from the blood circulation very early. But the ability to reach the blood supply is not the key. What is the key is what are the features of those sub populations that resist apoptotic signalling from immune cells a tissue cytokines that not only allow the metastatic cell to reside and thrive in a distant and hositle tissue.

I agree with all the interesting discussions here as the answer leads to various perspectives. As for cancer, it may begin in a specific cell type induced to change from its normal stage to the cancer cell due to aberrations in the normal cell's survival or apoptotic pathways leading to an abnormal growth of the cell along with structural and functional changes within the cell. Induced pluripotency or lack of normal differentiation

under abnormal situations may lead to cancer involving both genetic and epigenetic mechanisms such as mutations leading to activation of proto-oncogenes to oncogenes (Ras, Myc), and/or suppression of tumour suppressor genes (APC, p53) leading to perturbation of their signalling pathways. As cancer is a multistage, multihit process, as it advances various pathways may get involved and an array of protein-protein interactions (PPI) may take place depending on the type and stage of the tumour. Reasearch underway are continuously trying to understand the pathways involved as molecular pathways deciphered also shed light into newer discovery for cancer therapeutics such as in breast, lung, skin, endometrium and many more. In this site, http://www.genome.jp/kegg-bin/show_pathway?hsa05200

KEGG has provided nice overviews of some such cancer pathways. In an advanced stage more complexities arise as muitiple pathways and cross talks amidst them take place and as more mutations occur, more molecular pathways are disturbed.

Also, with the availability of high-throughput studies more and more data are available now and with various computational methods, analyses and meta-analyses of huge data is underway, researchers are now trying hard to predict molecular networks using such computational tools. Such studies shed further insights into deeper understanding of the cellular signalling from the normal to the abnormal states. Avi Ma'ayan's Lab focuses on such studies and these may be helpful for further reading such as

http://www.ncbi.nlm.nih.gov/pubmed/23586463

http://www.ncbi.nlm.nih.gov/pubmed/?term=Science+2005+Aug%3B+309(5737)%3A+1078-1083

I agree with Ericssons statement: „Cancer is not the final result of a pre-programmed progressive development of consecutive signalling pathways, or individual signalling events, it is the emergent property of multiple subtle changes in 'normal' signalling.“ But what means emergent?

On the one hand we have an abundance of information about the signalling pathways and mechanisms in cancer. But on the other hand we dont have a clear understanding concerning the “complex signalling acting”, the processing strategies of cancer cells, cancer organs, while we know a lot of singular signalling pathways on the molecular level of human cells?

Following the hint of Trosko, that “the more fundamental change in cancer research [as on the technical level] will be conceptual” (Trosko 2004), I argue for a fundamental differentiation betwenn signal-transduction and message-transduction based on the idea, that living entities – and cancer as well as a special form of living entity – cannot be fully accounted in terms of the principles and laws of physics and chemistry alone. Based on Barbara Mc Clintock's consideration in her Nobel lecture in 1983, that a goal for the future in biological science would be to determine the extent of knowledge a cell has of itself and how it utilizes this knowledge when challenged (Mc Clintock 1984) should be discussed the visionary thought of McClintock in actual cancer research; that means to confront us with the question what kind of knowledge and „communicative competence“ cancer cells (tissues, organs) have of themselves and how they utilize this competence within the process of carcinogenesis.

Pao Yen made a great point on the resting/non-resting states of blood supply to normal vs cancer cells. We've observed dilation of the blood supply in cases of cancer without reason behind it, without same to normal cells. Some of this might be explained by polypharmacy effects. Could medications for othet (non-cancer) purposes actually speed the growth of cancer?

Thanks to all debating participants for that exiting discussion. I would like to add some additional thoughts to it:

1. Cancer-progression is an evolutionary process

2. Cells require two distinct properties for this process:

- accelerated proliferation

- genetic instability

Mutations that foster these properties are linked to cancer initiation.

3. Due to the evolutionary cancer progression end-stage tumors inherit a heterogeneous population of different cancer cell traits (in solid tumors) with hundreds of different mutations

4. Heterogeneous cancer cell traits are a therapeutic problem because of multiple altered signaling pathways and therefore flexibility of growth

5. Following this argumentation it is to question if individualized cancer therapy will be feasible at all. Maybe the identification of key signaling pathways could lead to a breakthrough, if they exist.

6. Accepting the genetic heterogeneity of tumors and the impossibility to target them all, we could focus on heterotypic signaling between cancer cells and the supporting stroma. Cell signaling of stromal cells can be described in total without disturbing mutations and could lead to therapeutic strategies to deprive stromal support.

Yes, Mischa, and from our observations the Second Law of Thermodynamics fit into the list you so ably outlined.

all answers are clear. It is deppendent to thssue and kind of cancer,

Dear Mischa,

Interesting synthesis (if you would have references, it would be usefull).

The point 6 could be a good approach, but in perspective of new treatment, which could be the consequences of them targetting this cells (stroma) on the normal stromal cells and general function of tissues ? Strmal cells of a cancer tissue are there so different of normal stromal cells? (in general, cancer cells use fisrt normal stromal cell to build their tissue; but perhaps am I not uptodate).

But you could argue that point in classic chemotherapy as side effects are also generated because the treatments are not so specific of cancer cells.

Regards

Didier

Dear All,

The various points mentioned are correct, this discussion is very interesting and in the end is about personalized medicine.

Just a few additional comments and questions:

1.- The hematological malignancies are different and not in our discussion despite the fact that a big boost to the "personalized" Cancer therapy came from Chronic myelogenous leukemia and Gleevec. Rightly so, but.....CML is a stupid malignancy: one single mistake, bcr-abl translocation, is sufficient to create the disease.

Not to forget that the backbone of therapy in AML (anthracycline- ARA C), ALL (Vincristine- prednisone) and lymphoma (CHOP) are decades old. Additional Improvements have been substantial since, but far from personalized: (transplantation, radiotherapy, imaging, rituximab etc..). Myeloma has also greatly improved but is between stupid and smart cancer, closer to stupid.

2.- A solid tumor, when clinically diagnosed is an old disease. Choriocarcinoma is cured with old methotrexate and testicular cancer with platinum. All others, only the surgeon will cure the patient. We have hundreds of mutations on established advanced disease and there is no proof that correcting an abnormal signaling pathway will reverse the disease.

3.- Cancer stem cell heterogeneity +/- proven in renal cell carcinoma (NEJM 2012) and Colorectal Ca (Science 2013, J. Dick) might be a major problem of our still dream of personalized therapy.

4.- So far the so-called spectacular advancements of personalized cancer care are very modest: KRAS wildtype and cetuximab, the hype of ASCO a few years ago, improves only progression free survival and not overall survival. The same for most of the other new drugs: erlotinib added to gemcitabine in pancreatic cancer adds 10 days!! and on and on...

5.- Melanoma: very intersting the immunotherapy revival.

If you have hundreds of mutations in advanced solid tumors, you might have many abnormal proteins produced and some might be immunogenic...

Last point, cure through personalized medicine looks very promising in non oncology as we are dealing with genetically stable tissues and organs but might be an illusion in oncology. Whatever good arguments we have for stroma, epigenetics and other, the genetic instability of huge numbers of rapidly proliferating cancer cells gives an edge to the disease that is purely darwinian.

Excuse the length of this mail.

Nevertheless, never give up.

Re: Mario

I strongly agree to all your points. Maybe I can add one clarification to your no. 2.

According to mathematical calculations from a german cancer registry Hölzel et al. (2010) estimated that cancer progression from a primary to a more invasive phenotype to invade distant tissue must take place at the time when the growth of the primary reached about 100,000 cells. That is even less then 1qcm in volume. In conclusion every clinical prominent tumor would have an invasive phenotype and is likely to have acquired "advanced signaling".

Hölzel D, Eckel R, Emeny RT, Engel J: Distant metastases do not metastasize. Cancer Metastasis Rev. 2010, 29:737–50.

Re: Didier

One interesting reference:

Smith H a, Kang Y: The metastasis-promoting roles of tumor-associated immune cells. J. Mol. Med. (Berl). 2013, 91:411–29.

Mischa,

No problem about your point on early invasive phenotype at the preclinical stage. But that is a not a sufficient feature for metastatic evolution.There is more to it.

Think of the patients who do not progress to an advanced stage while treated and mostly cured after surgery only at an early stage in various solid cancers (e.g. >90% for stage I, >70% for stage II in colorectal Ca. Similar for others like breast and lung...).

Regards, Mario.

Mario, you are absolutely right but as I have said "it is likely". My point is that from the breach of the basal membrane to colonialisation of distant sites there is lot to do in this field to clarify these vague terms like "advanced signalling". Surely EMT is one important programm as already stated but what else?

Thanks Mischa

Regards

Didier

I think its better to say a evolutionary process in terms of starvation which drive the metastasis (cancer cell) to search the new area for nourishment or to minimize the metabolic load at one place therefore cancer cells shows some extraordinary advance signalling which makes them immortal.

I think that the research into the cancer stem/initiating cells, which is a very small proportion of tumor tissue (

Engin, where does the Kreb's cycle figure into these cells? My initial thought is cellular pH and its O2/CO2 environment might be key to eradication of cancer stem/initiating cells, but I am not a researcher in that area.

Dear Max, as far as i know there is no research on the ' Kreb's cycle of these special cells. It could really be good to do such research. pH is important, I agree. As is oxygen because these cells like less oxygen, compared to normal cells. Lots of things are still to do!

Correct spelling: Sir Hans Krebs, Krebs' cycle...

I am not aware of any relation to Krebs' cycle (citric acid).

Regards.

Thank you, Mario. You are correct.

The identification and development of molecular markers of late stage cancers and possible prognosis for metastasis are valuable targets that largely do not yet exist. Due to the complexity of cancers and the metastatic process, multiple markers will likely be needed. One hallmark of cancers is genomic instability so that chromosome aberrations tend to be associated with cancer cells over time. It’s possible that markers for instability would be useful as part of a panel of markers to distinguish cancer staging. Thus, signals associated with replication and damage stress would be candidates for late stage signaling.