Billions worldwide are infected with tropical worms.
Unsurprisingly, most of these people live in poor countries, kept poor by the effects of worm-related malnourishment.
What may surprise many is that worms also cause the majority of cases of some cancers in these countries.
Published in Frontiers in Medicine as a special article collection on parasite-associated malignancy, new research aims to inform prevention and treatment – and perhaps even turn worms against cancer.
Helminths (the word is derived from the Greek meaning “worms”; ref. 1) have plagued humans since before the era of our earliest recorded history.
The eggs of intestinal helminths can be found in the mummified feces of humans dating back thousands of years (2–4), and we can recognize many of the characteristic clinical features of helminth infections from the ancient writings of Hippocrates, Egyptian medical papyri, and the Bible (2–4).
These same helminthiases markedly altered the course of modern twentieth century world history (2, 4–7), especially in China during the Cold War, when the schistosome was known as “the blood-fluke that saved Formosa” (7) because acute schistosomiasis sickened Mao’s troops and aborted their amphibious assault of Taiwan (historically known as Formosa) just long enough for American ships to enter the Straits of Taiwan (5–7).
There are two major phyla of helminths.
The nematodes (also known as roundworms) include the major intestinal worms (also known as soil-transmitted helminths) and the filarial worms that cause lymphatic filariasis (LF) and onchocerciasis, whereas the platyhelminths (also known as flatworms) include the flukes (also known as trematodes), such as the schistosomes, and the tapeworms (also known as the cestodes), such as the pork tapeworm that causes cysticercosis (Table (Table1).1).
In 1947, Norman Stoll published a landmark paper entitled “This wormy world,” in which he set out to estimate the number of people infected with helminths worldwide (8).
Today, it is estimated that approximately one-third of the almost three billion people that live on less than two US dollars per day in developing regions of sub-Saharan Africa, Asia, and the Americas are infected with one or more helminth (12, 13).
The most common helminthiases are those caused by infection with intestinal helminths, ascariasis, trichuriasis, and hookworm, followed by schistosomiasis and LF (Table (Table1).1).
Practically speaking, this means that the inhabitants of thousands of rural, impoverished villages throughout the tropics and subtropics are often chronically infected with several different species of parasitic worm; that is, they are polyparasitized (12, 13).
The major human helminthiases and their global prevalence and distribution
For reasons not well understood, compared with any other age group, school-aged children (including adolescents) and preschool children tend to harbor the greatest numbers of intestinal worms and schistosomes and as a result experience growth stunting and diminished physical fitness as well as impaired memory and cognition (14).
These adverse health consequences combine to impair childhood educational performance, reduce school attendance (15), and account for the observation that hookworm (and presumably other diseases caused by parasitic worms) reduces future wage-earning capacity (16).
Hookworm and schistosomiasis are also important diseases during pregnancy, causing neonatal prematurity, reduced neonatal birth weight, and increased maternal morbidity and mortality (17).
Among some adult populations living in impoverished areas of developing countries, onchocerciasis is a leading cause of blindness and skin disease, while LF is a major cause of limb and genital deformities.
Such chronic, disabling, and often disfiguring effects of helminths translate into enormous poverty-promoting effects and represent a major reason why poor people remain mired in a downward cycle of destitution (19).
Adding to the global morbidity that results from human helminth infections are the observations that they have both direct and indirect effects on malaria and HIV/AIDS in developing countries. In sub-Saharan Africa and elsewhere, helminthiases are frequently coendemic with malaria (12, 20–22) and HIV/AIDS (12, 23–26).
Such coinfections have additive effects, such as severe anemia (21), and synergistic effects, such as increased transmission of the malaria-causing parasite, HIV, and/or increased susceptibility to infection with these pathogens as well as cause an exacerbated progression of these two killer diseases (12, 20–26).
The high medical, educational, and economic burden of helminth infections, together with their coendemicity with malaria and AIDS, provides an important rationale for launching a global assault on parasitic worms (13). However, the tools we currently have for controlling worm infections are limited; of the 1,556 new chemical entities marketed between 1975 and 2004, only four drugs – albendazole, oxamniquine, praziquantel, and ivermectin – were developed to treat helminthiases (4, 27).
Together with diethylcarbamazine (developed in the first half of the twentieth century) and mebendazole, these drugs represent almost our entire pharmacopeia for combating the most common infections in the world.
The dearth of available anthelminthic agents partly reflects the very modest commercial markets for drugs targeting human helminth infections and partly reflects how remarkably little we know about the unique biochemical metabolism of parasitic worms and the mechanisms by which worms evade human host defenses, establish chronic infections, and cause adverse maternal and child health (14).
Indeed, the diseases caused by infection with helminths are considered neglected tropical diseases, and the study of these diseases receives less than 1% of global research dollars (4).
Despite this, as we discuss here, recent advances by molecular and immunological helminthologists have indicated that helminths are a rich source of interesting molecules that could lead to innovation for almost all aspects of biomedicine.
We hope that such information might one day translate into the development of new drugs, diagnostics, and vaccines to combat infection with helminths as well as influence the development of new therapeutics for other human illnesses.
Worms cause cancer
Over a million worm species are classified as helminths. A single characteristic unites them: parasitism.
“Helminths take many forms, but all of them harm their host in some way.
In humans, they can live in the intestinal tract, urinary tract or bloodstream, causing a variety of illness from malnutrition to organ failure” explains co-editor of the research Dr. Monica Botelho of Portugal’s National Institute of Health.
In 2015 a more bizarre case of infection put helminths into the headlines: a man with HIV-AIDS died after his tapeworm contracted cancer and spread around his body. This remains the only such case ever recorded.
Meanwhile, scientists have known for decades that helminths can turn human cells into cancers.
“Three species of helminth are classified as class 1 carcinogens by the WHO,” adds Botelho.
“These are all designated trematodes—after the Latin name for the grisly feeding cavity with which they latch onto their host’s insides.”
Worm-related cancer is not just a fluke—it’s three
Trematodes are known informally as ‘flukes’. In this case however, they’re anything but.
“In endemic regions – predominantly sub-saharan Africa and Southeast Asia – flukes are responsible for the majority of all bladder and liver cancer cases,” says Dr. Joachim Richter, Associate Professor at Charité Berlin and co-editor with Botelho.
“Cancers arise in sites of fluke infection including the bladder wall and the bile ducts of the liver.”
But how does a worm cause cancer?
According the research collection, their feeding – and breeding – habits might be to blame.
“Flukes constantly wound and re-wound their host as they latch on with their feeding cavity, burrow through organs, and deposit eggs in the bladder wall.
This leads to chronic inflammation as the body tries endlessly to heal, meaning lots of cell division and so lots of opportunities for cancer-causing mutations to accumulate over years of infection.
“The flukes’ toxic toilet habits then add insult to injury.
“Worms and their eggs also excrete proteins that exacerbate this chronic inflammation, further promoting cell division as well as the blood vessel growth required to feed it,” adds Richter.
Hyper tapeworms protect hosts from cancer
Fluke infections and early stage cancers are often asymptomatic, so despite availability of anthelminthic drugs patients often present too late for curative treatment.
Fortunately, flukes have an Achilles’ heel: they require freshwater snails as a first host before infecting humans.
“Flukes have been successfully eliminated in Japan by economic development and the filling and drainage of snail habitats,” says Richter.
“Eradication efforts are underway in Thailand, which has the world’s highest rates of liver fluke infection and bile duct cancer – but some high-risk countries like Ethiopia lack a coordinated monitoring or prevention program for fluke-related cancer and need more help.”
Beyond eradication efforts lies another twist in the bizarre world of worms and cancer: helminths as a cure for malignancy.
“Many parasites, including some helminths like the liver fluke Fasciola hepatica, inhibit cancer growth in vitro.
Another of these – the ominously named ‘hyper tapeworm’ – is associated with a significantly lower rate of cancer in human hosts,” reports Botelho.
“In fact, there is evidence that proteins produced by hyper tapeworms as well as F. hepatica not only kill cancer cells directly—but might also enhance their host’s immune response to tumors.”
“Even cancer-promoting fluke proteins might be repurposed as treatments for other conditions: for example, those that promote new blood vessel growth could help resolve chronic non-healing wounds in diabetics, tobacco users, and the elderly.”
Gene-editing tool CRISPR/Cas9 shown to limit impact of certain parasitic diseases
More information: Monica C. Botelho et al, Editorial: Parasites and Cancer, Frontiers in Medicine (2019). DOI: 10.3389/fmed.2019.00055
Provided by Frontiers