Feeling the ‘heat’ from neighbors: Microenvironment driving cancers in the gut

Manisit Das

Not long ago Tamara mentioned in her OncoBites article that it is often hard to determine what factors drive cancer. Even after a mutation responsible for fueling cancer growth is identified, we do not always know how that mutation contributes to tumor formation. Understanding these mechanisms is however quite important. As we gain more insights into how the different players fit together in the puzzle, we can identify potential targets and therapies for cancer. Recent studies have brought forth new perspectives on how a previously known mutation associated with a condition called Peutz-Jeghers syndrome may actually drive it.

Tumor Suppressor genes (TSG) that encode for proteins like LKB1 play an important role in preventing cancer

Peutz–Jeghers syndrome (aka PJS) is a rare genetic disorder that results in the formation of polyps in the gastrointestinal tract. Polyps are generally benign, which means when they are removed, they do not usually grow back. However, those who suffer from PJS are found to be at an increased risk of several cancers. Normally, about 1 in 20 people run the risk of developing rectal or colon cancer. But those with PJS have an 8 times higher risk with 2 out of 5 patients developing these cancers. By 1998, we knew that a mutation and subsequent deficiency in a tumor suppressor protein called liver kinase B1 (LKB1) is associated with PJS. Tumor suppressor genes and the proteins they code regulate cell growth in normal conditions inhibiting tumor formation. When the functions of these genes are lost or inactivated, it removes the brakes that prevent tumor development, resulting in abnormal cell growth. Two independent studies authored by Poffenberger et al. and Ollila et al. have now shown that loss of LKB1 in immune cells and connective tissue cells (aka stroma) can bring a profound change in the gut microenvironment resulting in polyp formation.

Inflammation needs to be carefully regulated to protect us without causing harm

The researchers in these studies were asking how LKB1 loss results in the formation of polyps. They observed that loss of LKB1 leads to secretion of protein factors that can drive inflammation. If you have ever injured yourself or got a bug bite, you are probably familiar with how a wound site can heat up, turn red, sometimes swell, and be painful. While that sucks, these so-called ‘inflammatory’ responses directed by your immune cells are absolutely essential for eliminating the original cause of injury, to clear dead cells and damaged tissues, and facilitate healing. But moderation is key. While inflammation is a crucial process for wound healing and repair, too much inflammation can lead to diseases like autoimmune disorders where your body attacks its own healthy cells. Inflammation can also contribute to cancer. Continued inflammatory stimuli can lead to tissue damage beyond repair. When the tissue cannot be repaired, it has an increased chance of undergoing mutations, driving it towards cancerous changes. This creates a vicious cycle. So while short pulses of inflammation is a good thing, to help tissue repair, continuous inflammation facilitates reprogramming of the cell components in the tissue, promoting cancer, a ‘wound that never heals.’

What signals from the LKB1 deficient immune cells drive polyp formation? In mouse models, the studies identify two inflammatory protein factors called interleukin-6 (IL-6) and IL-11. These small proteins belong to a broader class of molecules called cytokines that play an active role in cell signaling, dictating how the cells around them behave. Secretion of IL-6 and IL-11 can lead to hyperactivation of a signaling pathway called JAK-STAT, whose disruption is known to lead to cancer development. When treated with JAK inhibitors, drugs that can interact with the above pathway lead to a reduction in the number of polyps in mice with dysfunctional LKB1 expression. Together, these results serve as an important example of how deregulation in immune system due to a dysfunction in normal gene activity may lead to the formation of benign tumors, eventually leading to cancer. The results of these studies with respect to PJS may stand true for a lot of other familial cancer syndromes, where the presence of a certain gene mutation can predispose the individuals to certain cancers.

PJS increases the cumulative risk of several cancers

So what do these studies mean for cancer therapy? As I mentioned before, PJS in itself is not cancer, but it increases the risk of several types of cancers. If we know how individuals develop PJS, and how the mutation in a gene changes the normal function of a cell, we have better chances of designing drugs to interfere at the nodes where the pathways so important for maintaining our standard physiological functions have gone rogue. We all know that in cancer, the earlier the disease can be detected, the better the clinical outcome for the patient. If we know who our enemies are, we can stop the villains with the hope to resist cancer even before it can take our bodies hostage!

Unfortunately, the quest of taming cancer is not as simple as it sounds. If you are following OncoBites closely, you are probably aware of that by now. While cancer prevention using chemical agents sounds promising, it is quite a hike before this approach becomes a clinical practice. There have been some attempts in the past to study chemoprevention in PJS with human patients. However, it is often difficult to find and recruit patients as the condition is quite rare. A study in the Netherlands managed to recruit only two patients and treated them with a drug against the mechanistic target of rapamycin (mTOR), another important signaling pathway whose overactivation can contribute to tumor development. One of the patients did not respond to the drug; while the other patient’s polyps stopped growing, he eventually refused treatment due to severe toxicity. While a clinical trial with only two patients is not a significant roadblock in search of chemopreventive routes for cancer, it does teach us a lesson or two. First of all, chemoprevention is not possible with a drug that is too toxic. We need to carefully perform toxicity studies before we pick another chemopreventive agent targeted at another signaling pathway. We have a vast spectrum of drug delivery technologies that can be used to guide where do the drugs go in the body after consumption, thereby reducing the toxicity.

The studies that we discussed today are yet another reminder to the idea that cancer is complex because it is the result of extremely complex biology going rogue. While changes in the function of cells that directly constitute an anatomical site within the body, like breast, colon, or pancreas, can drive tumor formation, influences and communications from neighbors like immune cells can contribute to cancer development as well. We have to take the lessons forward now and translate it to newer therapeutic approaches in treating, and even better, preventing cancer.  

Works Discussed:

Poffenberger, M. C., Metcalfe-Roach, A., Aguilar, E., Chen, J., Hsu, B. E., Wong, A. H., . . . Jones, R. G. (2018). LKB1 deficiency in T cells promotes the development of gastrointestinal polyposis. Science, 361(6400), 406-411.

Ollila, S., Domenech-Moreno, E., Laajanen, K., Wong, I. P., Tripathi, S., Pentinmikko, N., . . . Makela, T. P. (2018). Stromal Lkb1 deficiency leads to gastrointestinal tumorigenesis involving the IL-11-JAK/STAT3 pathway. J Clin Invest, 128(1), 402-414.

Hollstein, P. E., & Shaw, R. J. (2018). Inflamed T cells and stroma drive gut tumors. Science, 361(6400), 332-333.

Image Credits:

Inflammation of the intestine (Featured Image) https://www.crohnsandcolitis.com.au/inflammatory-bowel-disease/

Tumor Suppressor genes like LKB1 play an important role in preventing cancer. https://commons.wikimedia.org/wiki/File:Tumour_suppressor_genes_police_the_cell_cycle_and_downregulate_pro-cancer_signals.jpg

Inflammation needs to be carefully regulated to protect us without causing harm https://commons.wikimedia.org/wiki/File:Inflammation_scale.svg

PJS increases the cumulative risk of several cancers https://commons.wikimedia.org/wiki/File:PJS_Natural_History.jpg

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