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A Cancer Not of My Own

Diseases are inherently scary entities. The highly specialised and complex nature of the human body means that there is a hard-wired fear in all of us that this integrated system might be disturbed in some way. Individual diseases have individual fears associated with them. Viruses, with their ability to covertly subvert our health, terrify with their pandemic potential. Cancers and parasites breed a different type of fear – the inherent discomfort of knowing that our own cells are rebelling against us. The reprise we are given is that these diseases are inherently disparate in their characteristics – viruses cannot replicate without our cells as hosts and cancers are not infectious.

It is hoped that the discovery of certain strains of HPV as the causative agent for most cases of cervical cancer and the subsequent development of a vaccine may lead to disappearance of this cancer. CREDIT:
It is hoped that the discovery of certain strains of HPV as the causative agent for most cases of cervical cancer and the subsequent development of a vaccine may lead to disappearance of this cancer. CREDIT: Jan Christian

However, as our understanding of the causative factors of the diseases that threaten our existence has grown, this disparity has become increasingly blurred. With the discovery that viruses such as Human

Papillomavirus (HPV) can lead to the development of cancer in the tissues they infect, it became clear that we have barely scratched the surface when it comes to how these diseases relate to one another and cooperate to subvert that delicate systems that underpin our health. However, with discovery also comes opportunity, with a great deal of research now focused on exploiting these relationships in the develop of therapeutic and preventative practises.

 


Tapeworm Terror

Infections with H.nana, the most common human tapeworm, which infects up to 75 million people and whose prevalence in children may be as high as 25% in some areas (1), such as equatorial Africa, rarely cause significant health concerns.

H.nana_stained
Hymenolepis nana, shortened to H.nana and commonly referred to as the dwarf tapeworm, is the smallest tapeworm to infect humans, rarely growing larger than 40mm in length. CREDIT: Medical Pictures Info

H.nana is unique amongst tapeworms in that it can complete its entire life cycle in a single host. Typically, a parasite will exist in multiple hosts throughout different points in its life cycle. However, H.nana does not need to leave the human body at any point. Once an infection has taken its course, embryos are released into the intestine before re-infecting the very same cells from which they were released.

While, as previously mentioned, disease-causing H.nana infections are rare, it is also extremely uncommon to see an infection occur outside of the intestine – since the majority of the lifecycle occurs there. However, both of these were reported in a case study in the New England Journal of Medicine (2) in November 2015. They presented the case of a 41-year-old Colombian HIV-positive male who presented with fatigue, fever, cough and severe weight loss. Analysis of stool samples suggested an infection with H.nana.

A few things, however, didn’t quite match up – he was presenting with symptoms you wouldn’t expect with a tapeworm infection and his lungs and lymph nodes, not his intestines, were full of bizarre nodules. However, the greatest mystery was yet to come. When the cells from these nodules were analysed with high-power microscopes, it became clear that they were not of human origin. They were an abnormal size and lacked commonly expressed features of human cells. Researchers were further baffled when these masses were displaying clear signs of cancer – they were high undifferentiated, they had grown in a highly disorganised manner and had begun to invade nearby tissue, a process more commonly known as metastasis. Over the course of the period that the man was studied, around five months, the lesions grew and his condition continued to decline, before he eventually died of kidney failure.

In order to determine the mystery condition that lead to the patient’s death, researchers performed multiple analyses on the as-yet unidentified cells within the nodules. They used Polymerase Chain Reaction (PCR) technology, which scans for specific DNA sequences and makes multiple copies of that sequence, to determine exactly what the origin of the nodule cells were. It was to the great surprise of researchers when clear evidence of tapeworm DNA was identified. This prompted more substantial DNA sequencing of patient samples which, when compared to a known reference sample of H.nana, seemed to clearly identify the cells as being from tapeworm origin.

Questions still remained – just how did such bizarre tapeworm cells find their way to the lungs, the lymph nodes and beyond, and why had they formed what were essentially tumours? Further genome sequencing yielded some potential answers. The cells from the lymph node samples all displayed similar mutations that could have been behind the cancerous behaviour of the tapeworm cells. When genes are disrupted by mutations in DNA sequence, the proteins that these genes code for may be produced to an altered degree or may have a new, damaging function. It was clear that the mutations discovered in these H.nana cells were all in locations that could lead to cancer if disrupted.

The final piece in the puzzle came from re-visiting the appearance of the cells. It was noted that the cells in the lymph node samples looked a great deal like stem cells. These cells can replicate more proficiently than most cells and, in many ways, display characteristics of cancer cells – they replicate rapidly, lack any specific markers of developed cells and may be very motile. There is a great deal of thought that all human cancers arise from the populations of stem cells that support the maintenance of most of our tissues. Cancers are more likely to arise in these cells as they are replicating more frequently and hence errors during DNA replication, the most common cause of mutations, are more likely to occur and be passed on to all the cells that originate from these stem cells.

It is thought that the same process may have occurred in the tapeworm stem cells within the infected patient. Researchers came to the conclusion that the man’s HIV-positive status, and hence deficient immune system, meant that the tapeworm infection could continue unabated. Hence, the population of stem cells supporting the development of tapeworm tissues were more able to replicate out of control and therefore more likely to generate the mutations that are the basis of all cancers.

This intriguing case brought to the limelight a number of firsts and fascinating principles. This is thought to be the first evidence of the development of cancers in tapeworms and may in fact shed light on the fact that human cancers might have been misdiagnosed as parasite cancers causing damage to their human hosts. The considerations stemming from this research may be substantial. It is thought that current treatments may not be effective in clearing populations of stem cells, specifically in immunodeficient patients. This fascinating case brought to light a previously unheard of concept that complicated the cancer landscape, in which we are subject to the diseases of other organisms that call our body home.


Tasmanian Toil

A prime example of the shifting landscape of these diseases is the disturbingly named Devil Facial Tumour Disease, henceforth referred to as DFTD. This disease has torn through the Tasmanian Devil population in recent decades, severely reducing its numbers to the extent that extinction is a very real possibility. Numbers have dwindled by 70% since the disease was first identified 20 years ago and it was recently established that 80% of the current population is infected (3).

DFTD has been identified as a cancer originating in a class of cells known as neuroendocrine cells, which are involved in the hormonal response to stimulation by neurotransmitters. The disease presents as the growth of large tumours, known as lesions, around the face and neck of affected devils. These tumours can grow so large that they impact feeding and breathing and this, along with the spread of cancerous cells to other tissues, such as the lung, liver and heart, is the most common cause of death.

A Tasmanian Devil suffering from advanced DFTD, with extensive lesions on the face and neck. CREDIT: Save The Tasmanian Devil Program
A Tasmanian Devil suffering from advanced DFTD, with extensive lesions on the face and neck. CREDIT: Save The Tasmanian Devil Program

It was clear from the disease progression and genetic analysis of lesions that this was a cancerous disease. However, a few things did not add up. Firstly, the rapid spread of the disease throughout the population was more indicative of a virus than a new cancer and second, a strange pattern was beginning to present itself: genetic analysis of the cancerous cells in different devils revealed that they were completely identical to each other and, to make matters more confusing, they could not have originated from the infected devils. This lead to a fascinating first – evidence of a genetically distinct cancer that was being transmitted from animal to animal, rather than originating in and dying along with its single host (4).

The next thing that had to be established was just how a cancer could be spread into a similar manner to viruses or bacteria. It had been shown by two separate groups that isolated DFTD cells could be grown with little resistance in unaffected devils, so all that was missing from a completing the disease life cycle was determining the various ways that the DFTD cells found their way into new hosts.

Rudimentary exploration into Tasmanian Devil activity highlighted biting, both playful and aggressive, as a likely route of transmission. Discovery of DFTD cells on the canines of infected Devils and the high percentage of bites occurring around the head, consistent with the location of lesions, supports this hypothesised method of transmission.

DFTD poses a challenge to scientists that is not unique in its ramifications, but is highly unusual in its circumstances. The Tasmanian Devil population faces the threat of extinction from a rapidly emerging and evolving disease that combines the virulence of a virus and the deadliness of a cancer. As such, the solution will have to be an exceptional one. Currently, the few Devils that appear to display resistance are held in captivity for selective breeding programmes. Going forward, two clear challenges remain – firstly, the resistant population must be researched in order to determine just where this resistance comes from and second, it must be determined whether DFTD cells display any characteristics or markers that can be exploited in the production of therapeutics or vaccines that could halt the spread of this highly unusual disease.

One of the most important questions that remains is whether a similar disease could arise and affect the human population in a similar manner to that of the Tasmanian Devils. One of the crucial reasons why this disease arising in Tasmanian Devils was no coincidence is the fact that the degree of variety between cells in Tasmanian Devils is almost uniquely low.

Immune systems work on the basis of determining self vs. non-self, determining whether foreign objects are present in an organism and clearing them. This works for both large differences, such as the difference between human cells and bacterial cells, and for smaller ones, such as two different sets of human cells. It is this sensitive system that is the basis for processes such as rejection of donated organs and limbs. Tasmanian Devils display surprisingly low variation in the markers on the surface of their cells, meaning that it is extremely difficult for the immune system of a Devil to determine whether the foreign DFTD cells, that originated in a different, ‘case-zero’ Devil, are foreign or not, allowing them to grow unabated and for the disease to take hold. It is unlikely, therefore, that a disease of the nature of DFTD could arise in humans, but if both DFTD and the H.nana case show anything it is that our understanding of cancer is constantly shifting and that we should be prepared to be surprised.

‘Til next time…

Joe


References:

(1) Crompton DW. How much human helminthiasis is there in the world?. J Parasitol. 1999 Jun. 85(3):397-403

(2) Muehlenbachs A, Bhatnagar J, Agudelo C a., Hidron A, Eberhard ML, Mathison B a., et al. Malignant Transformation of Hymenolepis nana in a Human Host. N Engl J Med [Internet]. 2015;373(19):1845–52.

(3) https://en.wikipedia.org/wiki/Devil_facial_tumour_disease

(4) Murchison EP. Clonally transmissible cancers in dogs and Tasmanian devils. Oncogene [Internet]. Macmillan Publishers Limited; 27(S2):S19–30

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