Hi,

You may revert this arguemnt. In fact, we do have a good and strong immune system against cancer. From tumor (d)evolutionary point of you one may consider the loss of immunerecognition is an escape machanism for a tumor cell. For example, deletion of the HLA locus is often seen. Immunesupression, immunecompromised situations both led to high cancer incidence (see HIV, immunsupressed patients). Many other examples are ssen. Reactivation of the immune system is one of the target for cancer treatment. Several examples can be found for these on pubmed.

I hope this can give you another angel for thinking.

Best,

Karoly

Karoyl,

You bring up an interesting point. From an evolutionary standpoint, it is more of a tumor success versus a lack of adaptivity of our immune system.

I think the answer is much more simple and something Rob touched on: selective pressures revolve around breeding success. The average age of menopause is 51. Furthermore, there are significant increases in adverse obstetric outcomes beginning around age 35. Given that most non-hereditary cancers arise after this age, there simply isn't an evolutionary pressure to deal with it.

Karoyl is also correct in noting that evading the immune response is a well characterized trait that is necessary and acquired in most cancers.

Tumors induced by carcinogens in immunodeficient animals are rejected in normal secondary syngeneic recipients. On the contrary, tumors rised in normal animals kill secondary recipients possessing normal immune functions.. This well established fact is strong evidence corroborating existence of both immunological surveillance over tumor onset and selection of tumor cells under pressure of immune system. I think, main point here is that immune recognition in slowly evolving vertebrates is degenerative. This degeneracy appears as consequence of allelic diversification of MHC. Growing variety of allele-specific MHC binding motifs results in capability to present only part of anigenic peptides of viral and microbial pathogens in single individual. In whole population allelic diversification of MHC makes "safety net", allowing to catch modified pathogen in secondary host, making the evolution of pathogen in primary host useless. At the same time, the degeneracy makes easier the establishment of central tolerance to self. I agree with Rob, that the evolutionary pressure for effective immune surveillance of malignant cells may be weak, since most malignancies occur after reproductive period. Evident consequence for immune system is the need to use existing mechanisms, mainly antiviral immune defense, to reject transformed cells. However, the degeneracy make possible also the window for tumor escape, because not all tumor antigens arising as consequence of mutations of genes encoding oncogenic proteins can be recognized by immune system.

One may also ask: why don't we have more tumor suppressor genes? And the same answer will be: because of the evolutionary cost. Cancer is not such a load for vertebrate species as to loose fitness only to avoid it.

You are right, Rob! Recent review by Christian Hinrichs and Nicholas Restifo strongly endorses your statement.

https://www.researchgate.net/publication/258061317_Reassessing_target_antigens_for_adoptive_T-cell_therapy

Immunological surveillance ablates tumor cells carrying MHC/'mutant peptide' combinations visible to immune system. Remaining tumor cells can be recognized by immune system via expression of epigenetically arised tumor-associated (non-mutant) antigens, i.e. autoantigens. Certainly, stimulation of these responses can result in autoimmune disorders, because of the presence of these antigens in some normal cells. So, induction of "beneficial autoimmunity" suggested by Hans Stauss represents main goal of current studies targeted to develop efficient immunotherapies against cancer. Main problem is to find antigens targeting of which will result in minimal damage to vital functions.

Article Reassessing target antigens for adoptive T-cell therapy

My prompt answer would be: may be because tumor cells are our own. Perhaps the immune system have trouble realizing that the cells that are recognized as "self" are already "somebody else". More thoughtful answer would be, because tumor cells are good in killing natural killers and other apoptosis inducer cells. So, we are sleeping with the enemy and there is nothing to do. Well, I don't know... May be! Our colleagues can tell how right or wrong am I... It would be fun.

Dear Paula, NK cells are rather component of innate immune system, although there are some observations suggesting their more advanced adaptive-like role (fine specificity, memory, etc.). I think, NK cells begin to work too late, when tumor progression and the pressure of adaptive immune system have resulted to the absence of MHC class I molecules on tumor cells and inhibitory signals switch off. My personal experience in stidies of responses to allogeneic tumors does not support any recognizable involvement of NKs in these responses. I should noted also, that there are many cell types resistant to lysis by NK. I foresee, many colleagues will not share my scepticism in this field. Sorry!

Sorry I was just saying in general why do I believe the immune system isn't enough to control tumor cells. What I said was at the top of my mind. Perhaps I'm wrong and I would like to see how. So, show me.

"if a cancer down-regulates MHC1, this will help evade recognition by T cells, however the absence of MHC1 should activate NK cells, which recognize this symptom of evasion..."

Really, the loss of MHC class I molecules may be observed on late stages of tumor progression and this does not represent the majority of malignancies. If you look on collections of tumor cell lines, you will see, that only minor parts of them have deficient MHC class I expression (approximately 10%). This suggests that tumor escape may be mediated by the loss of MHC class I, but this has not key role for majority of tumors. The majority of tumor cell lines induces vigorous allogeneic responses targeted to tumor MHC class I molecules. These responses are sufficient for full destruction of tumor cells and indefinite survival of recipients. So, I can see not so much cases when NK could play significant role.

"inflammation are largely dependent upon neutrophil trafficking, and chronic inflammation is a requirement for the evolution of many (most) strains of cancer..." I would say, will see. In responses to allogeneic tumors neutrophils producing IL-12 and expressing CD80 and MHC class II can play significant role in enhancement of CD8 CTL responses and subsequent tumor rejection. Neutrophils are not uniform and can be differently differentiated to perform distinct functions.

"I also wonder if the cells of the immune system do not themselves become contaminated with the same pathogenic proteins and glycans displayed by the cancer cells, making recognition of 'non-self' very difficult".

My experience does not support this idea.

Jackson, you are not allowed to quote wikipedia.

As far as tumors escaping T-Cell response, 1 of 3 possible situations exist:

1.) Tumor cells are not suppressing sufficient antigens to elicit maximum CTls response

2.) Tumor cells are resistant to Granzyme attack by CTLs

3.) Tumors have a number of negative regulatory ligands for T-Cell receptors; down regulating T-Cell Function. This is especially prominent in many late stage tumors and these include: Fas-L and other ligands to induce apoptosis in T-Cells and natural killer cells.

This demonstrates that tumors have evolved many mechanisms to bypass our immune system; making tumor cells more evolutionary successful and apatable then our evolved CLTs

Dear William, you raise debatable questions and present them as established facts. Quite the contrary, mortality from oncological diseases decreases as result of campaign against smoking, introduction of new technologies of food storage and preparing a meal. You should take into account that advanced diagnostics now allows to reveal much more events of oncological diseases than it was possible in the past, 10 or 20 years ago. The same would be argued concerning gluten enteropathy. Therefore, "increased prevalence of cancer" in "younger patients" may be apparent, especially if you will consider decreased death-rate from cancers and another reasons in more old patients. It would be nice to hear the opinion of competent epidemiologist here.

Thank you, Willam! Questions are not so simple, as it would appear. Correct answers may be formulated taking into account many factors including diagnostics, mortality from another reasons, change in frequency of prevaling cancers, etc. These topics are out of my area of expertize. Sorry! Therefore, the participation of epidemiologist in this discussion would be very helpful.

I got some naive questions. Is it possible, that in industrialized countries hygienic status is to "high"? Therefore, germs are getting more resistant and evolve in higher rates and become more aggressive and tumorgenic? And on the other hand is the overall populations immune system of "richer" countries are not as fit as in "poorer" countries? And is there a lower evolutionary pressure in high industrialized countries, where a better medical supply leads to a less fitter population, getting more genetic and immunological instable, leading to "imbreeding-like" effects?

These are very complex questions, Daniel. The difference does exist. People in industrialized countries are more prone to so called atopic diseases, diabetes and some other autoimmune diseases. There is very popular and hot scientific field studying this as consequence of colonisation of gut by commensal microorganisms. "Inbreeding-like effects" seem unlikely to me due to highly increased mobility of people.

Thank you Dmitry.

I ment with "imbreeding-like effects" an accumulation of genetic mutations due to the low evolutionary pressure, which leads to an cancer promoting effect.

Dear Daniel, I would address you to beginning of this discussion. As I know, hereditary cancers do exist, but represent small part of overall incidence of cancer. So, I have some doubts to discuss this topic further, especially taking into account ethical considerations. Sorry! We need to do all, to exclude and successfully treat hereditary cancers, but unlikely the discussion of "evolutionary pressure" will be so helpful in relation to human beings.

Dear William, it may be you are right, but the concept seems sophisticated and unsufficiently proven. Will see. I would suggest much more relevant (it may be) idea, - the presence of 238U, 232Th and 40K in fuel. In developed countries this environmental factor may affect carcinogenesis much more directly.

@jackson, the importance of the microbiome is becoming more well understood each day; there does not seem to be a disease that it is not associated with.

However, its role as the major cause of most diseases is probably just a "fad;" that is all you seem to here about these days, the "microbiome."

Evidence today suggests that the microbiome is involved in almost all major diseases; going so far as to say that it is the leading cause of obesity/diabetes; which other research4 directly contradicts. . (article attached).

As dmitry mentioned, its direct role as a main cause of most cancer is probably not likely; however, its composition is probably altered in cancer patients; especially those undergoing some type of treatment.

http://www.nature.com/nature/journal/v444/n7122/full/nature05414.html

@Jackson, "especially those undergoing treatment."Thus,from this, I am arguing that maybe the onset of cancer/treatment is most likely responsible for its altered composition; which one of your articles implicitly indicates ;).

None of the articles you posted indicated that altered microbiome composition elicits a strong enough response to abrogate immune efforts in dealing with cancers; none of the articles, in fact, dealt with cancer at all. Sure, the microorganisms in the gut interact with the host.

And increasing susceptibility to cancer does not make the issue of primary concern with dealing with the actual development; for example, there are dozens of risk factors for cancer development, however, each of these risk factors alone does not prompt development. For example, High composition of alcohol is a risk factor for cancer development; however, alcoholism is not considered a primary cause of carcinogenesis.

These articles simply indicated that the microbiome may be involved with host metabolism and drug interactions; which with intensive cancer treatment would selectively favor those microorganisms that are involved in these metabolism processes, thus altering its composition to make the host more able to deal with these processes.

@ Jackson,

Again with your articles. Your articles are restricted to colon cancer development.

So what you are really arguing is that the microbiome plays an important role in colon cancer development.

According to the world health organization, 13 percent of people, world wide, die from cancer; colon cancers make up only 8 percent of the deaths.

Sure, the microbiome probably has an important role in the development of gastrointestinal cancers, seeing the importance of microorganisms in modulating digestive processes and the number found in the gastrointestinal tracko.

The colon contains most of the bacterial biomass; The colon is the most biological dense ecosystem in the world; with over 10^(12) bacterial cells per mL. Thus, the microbiome's primary contribution to cancer would be via the colon.

But for the other 92 percent of cancer deaths, microbiome's role is most likely diminished.

Additionally, the primary determinant of gut flora composition is age. So in the case of colon cancer, the direct mechanism would be increased age. This would ultimately change microbiome composition leading to increased risk for cancer development.

And according to the Colon Cancer Alliance, 90 percent of all colon cancer cases are people older than 50 years of age; so it is age that is the primary determining factor in colon cancer development

@Jackson,

You are asserting that an urban environment modifies the microbiome leading to systemic inflammation resulting in an immune system that is able to check the progression of cancer.

My argument: all the scientific evidence indicates that the microbiome plays an important role in colon cancer, and most likely is not involved in other types of cancers.

The problem with your line of reasoning is that it rests on so many assumptions that it is difficult to make a logical conclusion or one that is likely to happen.

Assumptions you are making:

*Most people that get cancer live in an urban environment

*system inflammation is a prerequisite for cancer development

*auto immune disorders are a prerequisite for cancer development.

*Changing micorbiome composition leads to chronic inflammation.

For example, do most people that develop cancers actually live in an urban environment?

Attached, I found an article that indicates that most cases of cancer in India are by those that live in rural areas; the studies indicates that 70 PERCENT of cancer cases in Indian are from rural populations(figure 5).

And roughly 70 percent of the Indian population lives in rural environments.

Indicating that cancer rates among these urban and rural populations are roughly equal.

Are auto immune disorders prerequisites for carcinogenesis?

Most likely not.

Does systemic inflammation always lead to cancer development?

Most likely results after cancer development

http://ispub.com/IJE/7/2/11985#

Jackson, please, stop your flood. In "traditional rural settings" people die in consequence of undiagnosed cancers, or much earlier for another reasons. I think, you turn up your RG score by useless chatter not being qualified specialist. in any area. It seems, you can not imagine that this chatter is very dangerous and offensive for many people, both good specialists, and really ill patients. Definitely, this portal NOT for you.

@ Jackson again with your sources.

Your sources primarily indicate that a healthy digestive process is helpful when combating cancer due to enhancing absorption of cancer therapeutics; which is understandable on a practical level.

None of articles demonstrate how changes in the microbiome cause the development of a cancer phenotype.

Article 1: indicates that microbiome influences inflammatory states.

*However, it also indicates that roughly 85 percent of cancers are NOT preceded by chronic inflammatory states; thus, most are not.

Article 2; indicates that germ free mice are more resistant to chemical therapy;

*This does NOT mean that germ free mice have a greater risk for developing a cancer phenotype.

*Does not indicate that most cancer patients actually have reduce microorganisms function during treatments.

Article 3: same as the second.

Article 4: Antibiotic over consumption correlated with cancer development.

*Does NOT indicate a study linking probiotics consumption and breast cancer reduction; it simply states that women who more regularly consumed antibiotics were more likely to develop breast cancer;

*HOWEVER, the mechanism by which antibiotics consumption may aid with breast cancer development is not discussed; correlation does not merit causation.

All other article: same arguments

The idea that cancer is a disease of industrialization is completely not true; cancer has been around as long as life as been around.

The first civilization to have documented records of cancer development is the Greeks and Roman/Greeks doctors were accustomed to treating cancer patients(article attached); hippocrates believe that excess black bile, depression as known now, caused cancer;

http://thechart.blogs.cnn.com/2010/10/14/how-the-ancient-world-dealt-with-cancer/