Bacteria and fungi can be found lurking in and around tumours. These microbial residents may be crucial to understanding how cancer develops and how to treat it.


Our bodies are thriving habitats for other life-forms. Our guts, mouths, noses and skin support diverse communities of microbes that can be both good and bad for our health. But in recent years scientists have been finding microbes in an altogether more surprising place – in tumours.


It is common to think of cancers as simply masses of a patient's own cells that malfunction and grow uncontrollably. They are in fact communities of many different cell types, which is part of the reason why cancers are so hard to treat – it is difficult to target them without harming healthy tissue too.


But tumours also play host to a collection of cells from other life-forms entirely – bacteria and fungi. Some thrive in the environment around a tumour while others live inside the cancer cells themselves.


Until recently, however, the role that these microbes play in tumours has not been clearly understood. Now scientists are starting to unravel whether these tumour-associated microorganisms are accomplices that assist cancer cells as they develop or just unfortunate bystanders caught up in the tumour. And the answers could provide new approaches to treating and preventing cancers.


Fusobacterium nucleatum is commonly associated with the mouth, but is also found in many tumours


In a 2017 study Ravid Straussman, a cancer biologist at the Weizmann Institute of Science in Rehovot, Israel and his team showed that some bacteria living inside human pancreatic cancers can protect the tumours by inactivating a common chemotherapy drug. They found that one particular class of bacteria, known as Gammaproteobacteria, could break down gemcitabine: a drug used to treat a number of cancers including those found in the bladder, breast and pancreas. This helped the tumours become resistant to the drug. When the team injected mice with colon cancer with the bacteria, the mice's cancers also became resistant to the drug. But when the researchers gave the mice an antibiotic alongside the chemotherapy drug, the resistance disappeared.

拉韋德·施特勞斯曼是以色列雷霍沃特的魏茨曼科學研究所的癌癥生物學家,他和團隊在 2017 年的一項研究發現,人類胰腺癌內部的某些細菌能使一種常見的化療藥物失去活性,以此來保護腫瘤。他們發現一種特殊的γ‐變形菌綱可以分解吉西他濱:這是一種用于治療多種癌癥的藥物,包括膀胱癌、乳腺癌、胰腺癌。這有助于腫瘤對藥物產生耐藥性。當研究團隊給患有結腸癌的小鼠注射這種細菌時,小鼠的癌癥也對該藥物產生了耐藥性。但當研究人員給小鼠聯合注射抗生素和化療藥物時,耐藥性消失了。

Further to these findings, research published in 2019 by a team at Tohoku University in Japan looked retrospectively at patients suffering from advanced cancers who were treated with either a chemotherapeutic drug alone and those who also received an antibiotic in addition to the chemotherapy in an attempt to prevent or treat an existing infection. They found that patients who were given an antibiotic had a better response to treatment. Although the study did not examine the amount of bacteria present in the cancer tissue of these patients, the researchers speculated that the antibiotics might have eliminated tumour-associated bacteria, which may have been interfering with the cancer treatment.

除了這些發現之外,日本東北大學的一個團隊于 2019 年發表的研究報告回顧了兩類癌癥晚期患者,一類僅接受化療藥物治療,另一類為了預防或治療現有感染,除了化療還接受了抗生素治療。他們發現接受抗生素治療的患者有更好的療效。盡管該研究沒有檢查患者的癌癥組織內存在的細菌數量,但研究人員推測,抗生素可能消滅了與腫瘤相關的細菌,而這些細菌可能一直在干擾癌癥治療。
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The studies offer a tantalising hint of what might be going on within tumours.


Straussman and his team are now hoping to build on these studies with a clinical trial involving patients with pancreatic cancer who failed their first line treatment. They will give patients an antibiotic known to act against Gammaproteobacteria, alongside a course of the chemotherapy drug gemcitabine, to see if the antibiotic improves their outcomes.


But bacteria might also play other roles in cancer beyond protecting tumours from drug treatment.


In 2020, Straussman's team looked at more than 1,500 human tumours across seven different cancer types: breast, lung, ovary, pancreas, melanoma, bone and brain. They found all of the tumour types were invaded by bacteria, which lived inside the cancer cells and some of the immune cells. Different tumour types had distinct communities of bacteria.

2020 年,施特勞斯曼的團隊研究了1500 多個人類腫瘤,涵蓋7類癌癥:乳腺癌、肺癌、卵巢癌、胰腺癌、黑色素瘤、骨癌、腦癌。他們發現所有類型的腫瘤都被細菌入侵了,它們存在于癌細胞和某些免疫細胞內。不同類型的腫瘤具有不同的細菌群落。

"Each of these bacteria have adapted to the unique tumour microenvironment in which they live," says Straussman. "In lung cancer, we demonstrated how people who smoke have more bacteria which can degrade nicotine – which is a smoke-related metabolite. In bone cancers, we see bacteria which metabolise hydroxyproline, which is a metabolite enriched in bone tumours."


In many cases it is still unclear whether the bacteria are helping the sufferer by keeping the cancer cells under control.


Bacteria found in some types of breast cancer, for example, can detoxify arsenate, a type of carcinogen known to increase the risk of breast cancer. Others can produce a chemical called mycothiol, which helps to reduce levels of harmful reactive oxygen molecules that can damage DNA.


There is growing evidence, however, that in some cases, the tumour-dwelling bacteria may actually be making cancers worse.


"More and more papers are coming out showing how they may be part of the carcinogenesis," says Straussman. The bacteria may also be altering the ability of the immune system to target and destroy cancer cells, he adds. "But we are really scratching the surface here." Much more needs to be done, he says, to study the effects that bacteria inside tumours have on the course of cancers.


There are already some clues. For example, a 2022 study by scientists in China suggests some bacteria in breast tumours might make it easier for cancer cells to spread to other parts of the body. The researchers found bacteria living inside breast tumour cells that were circulating in the blood of mice. These circulating cancer cells are shed from the primary tumour and can travel to other parts of the body, where they can metastasise and grow. However, as the tumour cells rattle around in the bloodstream, they are exposed to stress that causes some of them to break apart.

目前已經有些線索了。例如,中國科學家2022 年的一項研究表明,乳腺腫瘤中的某些細菌可能會使癌細胞更容易擴散到身體的其他部位。研究人員在小鼠血液中循環的乳腺腫瘤細胞內發現了細菌。這些循環癌細胞是從原發腫瘤中脫落的,可以轉移到身體的其他部位進行擴散和生長。然而,腫瘤細胞在血液中循環時會受到壓力,導致部分腫瘤細胞破裂。

The Chinese researchers found that the microbes inside these mobile tumour cells seem to protect them from some of the stress they experience. They appear to do this by helping to reorganise internal cellular support structures known as the cytoskeleton so the cells are more robust. When the scientists eliminated these bacteria from the mice tumours, the tumours appeared to lose their ability to metastasise, although the primary breast cancer continued growing.


"There is growing evidence that specific microbes in the gut, the skin, and other mucosal organs, as well as in tumours, can either promote tumour growth and progression, or alternatively antagonise it," says Douglas Hanahan, an oncologist at the Swiss Institute for Experimental Cancer Research in Lausanne, Switzerland, and the author of Hallmarks of Cancer: New Dimensions. However, the picture remains murky. "The landscape is very complicated, and while there are clues, there is no definitive clarity about who does what."


Other studies looked at Fusobacterium nucleatum, an oral bacterium associated with gum disease, but might also be associated with a number of different cancers. It seems these bacteria can migrate from the mouth to colorectal cancer cell through the bloodstream. Each bacterium carries specific particles on its surface that bind to the surface of cancer cells, allowing it to colonise them.


Once in place, the bacteria can accelerate the growth and spread of tumours, by hampering the immune system's ability to kill cancer cells. A protein produced by Fusobacterium nucleatum binds to a molecular control mechanism on the surfaces of human natural killer cells and T cells, which are both key parts of the immune system's defences against tumours. This binding inhibits the cells' ability to destroy cancer cells. The bacteria also deploy a molecular arsenal that makes cancer cells more resistant to chemotherapy.


Furthermore, Fusobacterium nucleatum's DNA has been found in human breast cancer samples. This suggests it also affects tumours elsewhere in the body. In one study, when the bacteria were introduced to mice with breast cancer, it accelerated the progression and spread of the disease. Giving the mice antibiotics prevented this.

另外,在人類乳腺癌樣本中也發現了具核梭桿菌的 DNA。這表明它也會影響身體其他部位的腫瘤。在一項研究中,當將細菌植入患有乳腺癌的小鼠體內時,它加速了乳腺癌的發展和擴散,但給小鼠服用抗生素防止了這種情況的發生。

It may seem tempting to include antibiotics in cancer therapies, but it is not as simple as that. Many of the microbes in our bodies are benign or even beneficial, so a brute-force antibiotic treatment could cause more harm than good, says Hanahan.


Instead, researchers must try to unravel the full complexity of the tumour-associated microbiome. Entire communities of microbes can be found within tumours, and they support each other in unexpected ways.


Many of the bacteria associated with colorectal cancers can work together to make the patient's condition worse


One such example revolves around the primary chemotherapeutic drug used to treat patients with colorectal cancer, 5-fluorouracil (5-FU). It seems to inhibit the growth of the troublesome Fusobacterium nucleatum. However, certain strains of Escherichia coli – commonbacteria found in the gut – render the drug inactive.

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Researchers led by Susan Bullman, a cancer microbiologist at the Fred Hutchinson Cancer Centre in Seattle, US, found that the inactive form of 5-FU no longer inhibited cancer in laboratory cell cultures. It also no longer prevented Fusobacterium nucleatum's growth. This led Bullman and her colleagues to hypothesise that patients who do not respond to 5-FU treatment may carry bacteria that inactivate the drug. These bacteria may allow Fusobacterium nucleatum the chance to flourish, making the patients' conditions worse.


At least 33 different types of cancer have now been found to have colonies of bacteria associated with them, thanks to techniques developed at the University of California, San Diego, that look for their DNA. The researchers believe the techniques could also be used to develop new ways of diagnosing cancer, by looking for the DNA from distinct tumour-associated bacteria in a patient's blood.

借助加州大學圣地亞哥分校研發的尋找細菌 DNA 技術,目前至少已發現 33 種不同類型的癌癥具有與其相關的細菌菌落。研究人員認為,通過在患者血液中尋找明顯與腫瘤相關的細菌DNA,這些技術還可以用來開發診斷癌癥的新方法。
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The team behind this study joined forces with Ravid Straussman for a 2022 study that revealed another type of microbe – fungi – living in cancer. They found fungi in 35 different types of cancer, many of which housed distinct combinations of species.

2022年,這項研究幕后的團隊與拉韋德·施特勞斯聯合開展了一項研究,發現了癌癥中的另一種微生物——真菌。他們在 35 種不同類型的癌癥中發現了真菌,其中許多癌癥含有明顯的物種組合。

"We found that tumours which have more bacteria also have more fungi, and ones with less bacteria have less fungi," says Straussman. "We can only hypothesise at this point that some tumours are more restrictive for the presence of microbes in them and some are more permissive."


Just as with bacteria, some of these fungi appear to be manipulating the immune system in the tumour's favour. The fungus Malassezia globosa has been found to speed up the development of one form of pancreatic cancer. The same fungi have also been found in breast cancer patients who tend to have shorter overall survival, according to work by Straussman and his University of California, San Diego colleagues. Other research has found that some fungi present in pancreatic cancers hijack parts of the immune system to promote tumour growth.


A 2022 study also showed that stomach cancers rich in Candida fungi show increased expression of tumour genes that promote inflammation and that colon tumours rich in Candida DNA are more likely to be metastatic. This "might be because increased numbers in Candida may be associated with loss of gut epithelial barrier [the cells lining the gut]," says Iliyan Iliev, a microbiologist at Cornell University, whose team conducted the research.

2022 年的一項研究還表明,在富含念珠菌的胃癌腫瘤中,引起炎癥的基因表達有所增加,而富含念珠菌DNA 的結腸腫瘤更有可能發生轉移。這“可能是因為念珠菌數量的增加可能與腸道上皮屏障(腸道內壁細胞)的喪失有關”,康奈爾大學的微生物學家伊利揚·伊利耶夫說道,他的團隊進行了這項研究。

Despite the rapid pace of these findings, many questions still remain about the relationship between tumours and the microbes that live in them. Do the microbes play a role in the development of the tumour in the first place? Or are they simply opportunistic residents that have adapted to protect their cancerous home when they find one? And can this microbe community be harnessed to help us in our fight against cancers?


In years to come, targeting tumour microbes may become as important as going after the cancer cells themselves, leading to earlier diagnoses and even new treatments. But that work has only just begun.