Are Tumours Spreading? Cancer as an infectious disease

This week saw one of the strangest scientific discoveries in the last few months. An article was published on 5th November in the New England Journal of Medicine detailing a case study of a HIV positive man presenting with fever and weight loss who, after several months of unsuccessful treatment, passed away from unknown causes1. Extensive post mortem analysis found malignant tumorous masses, in his lungs and lymph nodes, of non-human origin. Whilst this is beginning to sound like the opening plot of a cheesy horror film, the cells were found to originate from a species of tapeworm, known as Hymenolepis nana (or Dwarf tapeworm), endemic to the region. To my knowledge, this is the first documented case of zoonotic transmission of cancer. Cancer is typically a non-infectious disease, however, there are some notable examples of transmission of tumorigenic cells between individuals of the same species.

Transmission of tumours from human to human is not uncommon. Patients who receive organ donations regularly inherit previously unidentified tumours from their donors2. The progression of the tumours is aided by the necessity for transplant patients to take immuno-suppressive drugs to prevent organ rejection. However, the circumstances don’t have to be as extreme as an organ transplant. Children are capable of contracting  cancer in utero from their mother3. The high level of genetic similarity between mother and child, and the lack of immunological education in the early foetus makes vertical transmission possible albeit rare. Perhaps the most bizzare example of human to human transmission is the case of a surgeon who became infected with the tumour of a patient he was operating on after sustaining an injury during the operation4.

Sharing of tumours can also be seen in other species. In both dogs and Tasmanian devils transmission of cancer cells between individuals is highly common. In the case of dogs the cells are transmitted sexually, whilst in Tasmanian devils common face biting behaviour allows for the transfer of malignant cells. Due to incredibly low genetic diversity within both species the transmitted cells are not recognised as foreign and therefore do not trigger the host’s immune system5.

But how did our Colombian man become host for tape worm tumours? Well, his HIV status appears to be the key factor. He had been diagnosed as HIV positive nearly eight years prior to his death and was potentially infected many years before that. At this late stage of infection his ability to generate an immune response would have been severely compromised. This had serious consequences, firstly it may have caused the tapeworm to develop abnormal growths normally limited in healthy people. Secondly, it prevented his body from recognising and responding to the invasive cells that broke free from the worm and disseminated throughout his body. Had the HIV virus not made him severely immunocompromised his immune cells would have rapidly engulfed and destroyed the invading worm cells.

So, should we start thinking of cancer as an infectious disease? In the developed world the low exposure to parasitic worms and the relatively low HIV rate mean the chances of a similar case occurring in say London or Rome are almost non-existent. However, in the developing world similar cases may be highly prevalent with these events previously being unidentified due to limitations in local healthcare. Identifying zoonotic cancers may be crucial when considering treatment options in the future. Furthermore, the potential to develop tumours adds a further dimension of risk to infection with parasitic worms.

References:

  1. Muehlenbachs. N Engl J Med (2015) 373, 1845-1852
  2. Penn. Ann Transplant (1997) 2, 7-12
  3. Osada. Cancer (1990) 65, 1146-1149
  4. Gartner. N Engl J Med (1996) 335, 1494-1497
  5. Murchison. Oncogene (2009) 27, S19-S30

N.B. unfortunately I couldn’t find the original source of the image to credit

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Sniffer Worms: A Universal Effective Low Cost Method for Detecting Cancer?

A Highly Accurate Inclusive Cancer Screening Test Using Caenorhabditis elegans Scent Detection

Cancer, in almost all its forms, is an age associated disease. A given cell accrues genetic damage over time until it breaks free of the molecular shackles that maintain a healthy homeostasis. As our molecular safeguards are numerous this process takes time which explains why incidence of cancer increases almost exponentially with age (1). The intrinsic problem with a progressive, (and initially) slow moving disease is that it can remain asymptomatic and therefore undetected until it is too extensive to treat effectively. Melanoma is a excellent example as 95% of patients diagnosed with stage 1A melanoma will live for more than 5 years after diagnosis, however, once it has reached stage 4 as few as 5% of people will last the same amount of time (2).

With this in mind, identifying low cost, effective and largely universal methods for early diagnosis of cancer is a central theme in current biological research. Hirotsu et al (2015) attempted to develop what they refer to as the ‘Nematode Scent Detection Test (NSDT),’ which involves using roundworms to sense distinctive odours reported to emanate from tumours.

They began by exposing the nematode species Caenorhabditis elegans to media that had been used to culture either one of a host of cancer cell lines or non-tumourigenic human fibroblasts. Worms were found to be specifically attracted to media used to culture cancer cells and were not attracted to fibroblast conditioned media. Ancillary to this, the authors found that ODR-3 mutant C. elegans showed no attraction to cancer supplemented media. ODR-3, expressed by AWA and AWC olfactory neurones, is central to the attractive component of the worms’ olfactory system. When patients’ samples were used in place of cell lines the same response was observed. Combined, these data indicate that the worms respond specifically to odours generated by the cancer cells.

The authors next looked to determine whether this attraction could be manipulated for clinical use. When offered urine from patients with cancer or from tumour-free individuals worms were again found to be specifically attracted to the samples from cancer patients. This was true even of urine from early stage individuals. Using calcium imaging they demonstrated increased activity of AWA and AWC neurones in response to patient samples; confirming a role for the olfactory system in detecting cancer specific odours.

Using 460 urine samples, 242 of which were from cancer patients, the authors sought to establish the sensitivity of the NSDT. Stringent analysis found that the NSDT had a sensitivity of 95.8% and whilst this decreased with earlier stage cancers, their test was considerably more sensitive than other established markers. The test was also not influenced by the sex of the patient, other physical complaints or their medical regiment.

To summarise, Hirotsu and colleagues have identified and begun to optimise an innovative, novel, non-invasive method for identifying cancer at early stages. Nematode worms are easily maintained in laboratories around the world where the serve as a popular model organism. They therefore present themselves as a simple low cost tool in cancer diagnosis. However, more work is required to distinguish the specific odours produced by cancer cells. Additionally, the worms cannot indicate the organ from which the cancer originates and will have to be combined with other tests. Despite these caveats the future of the humble nematode as a diagnostic tool looks promising.

References:

(1) Cancer Incidence By Age – CRUK

(2) Melanoma Survival Stats – CRUK

(n) Hirotsu et al (2015) PlosONE, 10doi:10.1371

Image Credit:

HeLa (cancer) cells captured using 2-Photon fluorescence

Thomas Deerinck of the National Center for Microscopy and Imaging Research, La Jolla, CA, USA

A Novel Target for a Malaria Vaccine?

Antibodies to PfSEA-1 Block Parasite Egress from RBCs and Protect Against Malaria Infection

Hundreds of millions of people worldwide are infected with the malaria parasite. Of the five species of Plasmodium that infect humans, P. falciparum is the most deadly. Annually, malaria is responsible for up to one million deaths, the majority of which are young children. Despite this, no vaccines currently exist targeted specifically to children. Of great concern is the fact that of the majority of vaccine candidates are based upon only four antigens. Therefore, there is a great need for novel antigen targets. Raj et al (2014) aimed to use information derived from individuals in areas where P. falciparum is endemic to identify a novel malarial antigen.

Using plasma from 2-year-olds they identified three antigens specifically targeted by children resistant to the parasite. One of these, Plasmodium falciparum schizont egress antigen-1 (PfSEA-1), appeared to be essential for blood stage replication. Using an ELISA the authors found that plasma from resistant individuals showed a 4.4 fold greater recognition of PfSEA-1 than plasma derived from susceptible individuals. When parasites were treated in vitro with IgG raised against recombinant PfSEA-1, or with anti-PfSEA-1 derived from human serum, their growth was significantly reduced compared to untreated controls. 

To identify where PfSEA-1 is acting the authors used immunofluorescence microscopy and immunogold transmission electron microscopy. PfSEA-1 appeared to localise to the membranes of late schizont infected red blood cells. This localisation pattern combined with its requirement for blood stage development suggested that PfSEA-1 may be involved in egress of the schizonts. Indeed, immunodepletion of PfSEA-1 in vitro resulted in a significant reduction in parasite egress, demonstrating a crucial role for this protein in the parasite life cycle.

The authors then looked to determine the protective potential of vaccination with SEA-1. Mice were vaccinated with recombinant SEA-1 from P. berghei as this strain causes extreme lethality in mice. Three different strains of mice were used and all showed reduced parasite content in the blood compared with controls. Furthermore, vaccination resulted in a ~2 fold increase in survival. Therefore, SEA-1 presents a promising target for the development of vaccines. The authors support this by analysing IgG levels of resistant and susceptible individuals in two human populations. Expression of anti-PfSEA-1 IgG was able to predict resistance to malaria with individuals showing significantly reduced parasite density. This is particularly important as current vaccine candidates such as MSP-3 could not predict resistance.

To conclude, Raj et al (2014) have identified, and begun to characterise, a novel candidate for vaccines against the deadliest form of malaria. PfSEA-1 plays a crucial role in parasite egress with its depletion disrupting the parasite lifecycle. Vaccination of mice with recombinant SEA-1 improves survival and expression of anti-PfSEA-1 IgG predicts resistance in humans. This paper demonstrates the power of combining field and lab based research and provides a paradigm for identifying novel target antigens for vaccines not only against malaria but against all infectious diseases.

Reference:

Raj et al, (2014) Science, 344, 871-877

Image Credit:

James Gathany Content Providers