Mystery Rays from Outer Space

Meddling with things mankind is not meant to understand. Also, pictures of my kids

April 9th, 2009

Why are different tumors the same?

Hierarchical clustering of breast carcinomas, Turashvili et al 2007
Hierarchical clustering of breast carcinomas1

Something that’s puzzled me for years is why the same kinds of tumors tend to have the same kinds of immune evasion mechanisms. And I’m not going to give an answer, just trying to share the confusion a little.

What I mean is this:

It has been demonstrated that human tumors of distinct histology express low or downregulated MHC class I surface antigens … The distinct frequency of MHC class I abnormalities is caused by total HLA class I antigen loss, HLA class I down-regulation as well as loss or down-regulation of HLA class I allo-specificities. However, the frequency and mode of these defects significantly varied between the types of tumors analysed and could be associated in some cases with microsatellite instability. 2

(My emphasis) As I’ve noted here several times (most specifically here) tumors very often evade the immune system as they mature. Cytotoxic T lymphocytes (CTL) can control tumors in the tumors’ eary stages, but by the time we detect a tumor clinically the tumor is almost always resistant to the immune system. They do this in various ways, including inducing regulatory T cells, but also by mutating themselves to make themselves invisible to CTL (and other components of the immune system, but let’s keep it simpler for the moment).

There are a myriad ways for a tumor to become invisible, at the molecular level.  The MHC class I antigen presentation pathway is long and complex, and for any partiuclar tumor there are likely to be many different bottlenecks, points of attack.  Since tumors are all independent events3, so at first, and even second, glance, there’s no obvious reason why tumors of the same type should find a similar approach.  That is, just because two colon carcinomas look the same histologically in two different individuals, there’s no link between them.  4 Why should colon carcinomas avoid CTL using one set of mutations, while, say, breast cancers use a different set of mutations? Yet apparently, that’s what tends to happen; for example:

Mutations or deletions in β2-m were detected in colon carcinoma (21%), melanoma (15%) and other tumors (<5%). So far, no mutations in β2-m have been found in RCC lesions, bladder and laryngeal tumors despite MHC class I loss or downregulation. … haplotype loss was found in head and neck squamous cell carcinoma (HNSCC) with a frequency of 36%, whereas in renal cell carcinoma (RCC) LOH only occurs in approximately 12% of tumor lesions analyzed. 2

If we saw these patterns only with virus-associated cancers, such as cervical carcinomas and even hepatic carcinomas, there would at least be a common link, but these tumors are not (as far as we know) caused by viruses in humans.

Part of the answer may be that the particular oncogenes associated with different tumor types lead to particular transcriptional hot-spots, and being a transcriptional hot-spot makes the region a mutational hot-spot as well, but at least as I understand it that’s not enough to account for the trends.

So why are particular MHC abnormalities linked to tumor type?  Anyone?

  1. Turashvili et al. BMC Cancer 2007 7:55   doi:10.1186/1471-2407-7-55[]
  2. Seliger, B. (2008). Molecular mechanisms of MHC class I abnormalities and APM components in human tumors Cancer Immunology, Immunotherapy, 57 (11), 1719-1726 DOI: 10.1007/s00262-008-0515-4[][]
  3. barring such weird things as canine transmissible venereal tumor and Tasmanian Devil facial tumors; see here for more on those[]
  4. The comparison is, of course, viruses.  A herpesvirus of chickens, and one of humans, may both use immune evasion mechanisms, but they have a common ancestor even if it’s a couple of hundred million years ago.[]
April 6th, 2009

Inflammation and cancer: Proof that the universe hates us?

Metchnikov - Lecons sur la pathologie
Metchnikov: “Lecons sur la pathologie” (1892)

There are times when you just feel like the universe is out to get you. For example, we know that inflammation can drive tumor formation; but a paper just came out that suggests reducing inflammation can also drive tumor formation. 1 It doesn’t seem fair.

I’ve previously mentioned the link between inflammation and tumorigenesis, which is probably at least partly because the inflammation produces reactive oxygen and nitrogen species (RONS ) that are tumorigenic.

I’ve also talked about the link between reduced inflammation and ongoing tumors (for example, here, here, and here). What seems to be going on here is that regulatory T cells (TRegs) are induced by tumors, and these TRegs shut down anti-tumor immunity.

So far, these findings aren’t really contradictory. Increasing inflammation before a tumor is present makes tumors more likely to form. After the tumor has formed, reducing inflammation makes the tumor more likely to persist. The universe-is-against-us part comes from the suggestion that reducing inflammation (via TRegs) before tumor formation, also makes the tumors more likely to form.

This may be a special case. The paper from Philip Dennis’s group 1 looked at a specific set of cancers, those associated with K-Ras mutations (linked to smoking-induced lung cancer). K-Ras activation itself triggers inflammation (for reasons I, at any rate, don’t understand). When K-Ras is activated, as well as inflammation, TRegs move into the area, and presumably reduce the inflammation. Depleting the TRegs (and therefore increasing the inflammation) decreased the number of tumors by 75% — the opposite of what you’d expect if inflammatory RONS were driving tumorigenesis.

Smoking / cancer

A common feature linking smoking induced K-Ras mutations in human lung cancer and preclinical models driven by tobacco carcinogens that cause K-Ras mutations is inflammation. In both cases, the presence of Foxp3+ cells is likely important for limiting the extent of inflammation and tissue damage, albeit at a potential cost of promoting tumorigenesis. 1

In later-stage tumors the situation became more consistent with other work — getting rid of TRegs reduced the tumors, suggesting that these tumors were depending on TRegs to prevent immune clearance:

Aggressive and invasive K-Ras-induced adenocarcinomas (IO33 and K-RasLA2) remained sensitive to more direct targeting of Foxp3+ cells through a neutralizing anti-CD25 antibody or genetic deletion. This indicates that direct Treg cell depletion strategies that are being evaluated clinically could have therapeutic value in more advanced stages of K-Ras driven lung cancer. 1

My question here is whether the early inflammation is kind of a red herring. Could the TReg depletion in the early stages be reducing the anti-tumor immune response in a specific way, just as in the later stages of tumor formation? That is, could the TReg depletion lead to a tumor-specific immune response, which prevents tumors from forming? In this case the inflammation could still be driving the tumor formation, but the increase in tumor formation would be outweighed by the simultaneous increase in anti-tumor immunity. I don’t know quite how to test this, but perhaps doing the same experiment in mice lacking, say, CD8 T cells might be interesting. (Such mice should still have the early inflammation and the TRegs, but may have a less effective immune response. It’s not a perfect experiment, though, for reasons that are probably too complex to go into here.)

  1. Granville, C., Memmott, R., Balogh, A., Mariotti, J., Kawabata, S., Han, W., LoPiccolo, J., Foley, J., Liewehr, D., Steinberg, S., Fowler, D., Hollander, M., & Dennis, P. (2009). A Central Role for Foxp3+ Regulatory T Cells in K-Ras-Driven Lung Tumorigenesis PLoS ONE, 4 (3) DOI: 10.1371/journal.pone.0005061[][][][]
April 5th, 2009

Hyena blogging

Spotted hyenaWhile visting friends yesterday to watch MSU kick UConn ass in the Final Four1 I learned about the wonderful MSU hyena blog. MSU researcher Kay Holekamp has been studying spotted hyenas for many years; this blog is from their field camp in the Masai Mara National Reserve in Kenya.  Amazing pictures, great stories.

I don’t think I’ve met Holekamp herself, but a couple of her students took my grad immunology class last year; they’re interested in using MHC to identify hyenas, and in hyena immunity in general:

Spotted hyenas seem to be particularly adept at dealing with microbes that would make you or I extremely sick. … If the behavior of avoiding rotting meat is an effective way of avoiding infection, why are hyenas so willing to eat it? … I am particularly interested in finding out how the hyena immune system is able to withstand the inexhaustible onslaught of microbes that seeks to exploit them.

  1. Translation for non-US audience: College basketball[]