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.

細菌和真菌潛伏在腫瘤內部和周圍,這些微生物居民對于我們了解癌癥的形成機制和治療癌癥可能至關重要。

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.

我們人體是其他生物繁衍的棲息地。我們的內臟、嘴巴、鼻子、皮膚養活著各種微生物群落,它們對我們的健康既有利又有弊。但近年來,科學家們在一個完全出乎意料的部位——腫瘤中發現了微生物。

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.

人們通常認為,癌癥只是患者自身的大量細胞出現故障和生長失控。其實癌癥是由許多不同類型的細胞組成的群落,這也是癌癥難以治療的部分原因——很難在不損傷健康組織的情況下靶向消滅癌細胞。

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.

但腫瘤也完全是其他生物細胞的宿主——細菌和真菌。一些在腫瘤周圍的環境中茁壯成長,另一些則存在于癌細胞的內部。

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.

但直到最近,科學家一直沒有搞清楚這些微生物在腫瘤中發揮的作用?,F在科學家著手揭開這個謎團,與腫瘤相關的微生物是癌細胞生長的幫兇?還是只是不幸卷入腫瘤中的旁觀者?答案也許能提供治療和預防癌癥的新方法。


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

具核梭桿菌通常與口腔相關,但也存在于許多腫瘤中。

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.

這些研究為腫瘤內可能發生的情況提供了誘人的線索。

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.

施特勞斯曼和他的團隊現在希望在這些研究的基礎上,對一線治療失敗的胰腺癌患者進行臨床試驗。他們將給患者服用一種已知能夠對抗γ‐變形菌的抗生素,同時服用一個療程的化療藥物吉西他濱,以觀察抗生素是否有助于改善他們的療效。

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

但細菌不僅保護腫瘤免受藥物治療,還可能在癌癥中發揮著其他作用。

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."

“其中的每一種細菌都適應了它們所在的獨特的腫瘤微環境”,施特勞斯曼說道?!霸诜伟┲?,我們發現吸煙者擁有較多可以降解尼古丁的細菌,尼古丁是一種與吸煙相關的代謝物。在骨癌中,我們發現了代謝羥脯氨酸的細菌,羥脯氨酸是骨腫瘤中富含的代謝物”。

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

在許多情況下,科學家仍不清楚細菌是否通過抑制癌細胞來幫助患者。

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.

例如,在某些類型的乳腺癌中發現的細菌可以清除砷酸鹽,它是一種已知會增加乳腺癌風險的致癌物質。還有些細菌可以產生一種叫做真菌硫醇的化學物質,它有助于降低有害的活性氧分子的水平,而活性氧分子會破壞DNA。

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

然而越來越多的證據表明,在某些情況下,腫瘤內的細菌可能會使癌癥惡化。

"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.

斯特勞斯曼說:“越來越多的論文表明,它們可能是致癌因素之一”。他補充道,它們還可能改變免疫系統靶向消滅癌細胞的能力?!暗覀兇_實只是淺嘗輒止”。他表示為了研究腫瘤內的細菌對癌癥病程的影響,還有很多工作要做。

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.

中國研究人員發現,這些轉移的腫瘤細胞內的微生物似乎保護它們免受部分壓力。微生物似乎通過重組被稱為細胞骨架的細胞內部支撐結構來實現這一點,從而使腫瘤細胞更加堅固。當科學家消滅小鼠腫瘤內的細菌時,腫瘤似乎失去了轉移能力,但原發的乳腺癌仍在繼續生長。

"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."

位于瑞士洛桑的瑞士實驗性癌癥研究所的腫瘤學家、《癌癥的特征:新維度》一書的作者道格拉斯·哈納漢表示:“越來越多的證據表明,腸道、皮膚、其他粘膜器官、腫瘤內部的特定微生物可以促進或抑制腫瘤的生長和發展”。然而,情況仍然不明朗?!扒闆r非常復雜,雖然有線索,但尚不明確哪種細菌起什么作用”。

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.

其他研究著眼于具核梭桿菌,這是一種與牙齦疾病相關的口腔細菌,但可能也與許多癌癥有關。這些細菌似乎可以通過血液從口腔轉移到結直腸癌細胞中,每種細菌的表面都帶有特定的顆粒,這些顆粒與癌細胞的表面結合,使這種細菌寄生在癌細胞上。

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.

一旦寄生到癌細胞上,具核梭桿菌就可以抑制免疫系統消滅癌細胞的能力,從而加速腫瘤的生長和擴散。具核梭桿菌產生一種蛋白質,它與人類的自然殺傷細胞和T淋巴細胞表面的分子調控機制相結合,這兩者都是免疫系統防御腫瘤的關鍵部分。這種結合抑制了細胞消滅癌細胞的能力。這些細菌還部署了一種分子武器,使癌細胞對化療具有更強的抵抗力。

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.

在癌癥治療中加入抗生素似乎很誘人,但事情沒那么簡單。哈納漢說,我們體內的許多微生物都是良性甚至有益的,所以暴力使用抗生素治療可能弊大于利。

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.

相反,研究人員必須設法揭開腫瘤相關微生物組的全部復雜性。腫瘤內可以找到整個微生物群落,它們以意想不到的方式相互支持。


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

許多與結直腸癌相關的細菌可以共同作用,使患者的病情惡化。

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.

其中一個例子涉及用于治療結直腸癌患者的主要化療藥物5-氟尿嘧啶。它似乎可以抑制麻煩的具核梭桿菌的生長。然而,某些大腸桿菌菌株(腸道中常見的細菌)會使藥物失去活性。
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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.

美國西雅圖弗雷德·哈欽森癌癥研究中心的癌癥微生物學家蘇珊·布爾曼帶領的研究人員發現,失去活性的5-氟尿嘧啶不再抑制實驗室細胞培養物中的癌癥,也不再抑制具核梭桿菌的繁殖。布爾曼和她的同事由此推測,對5-氟尿嘧啶治療沒有效果的患者可能攜帶使藥物失活的細菌。這些細菌可能使具核梭桿菌大量繁殖,從而使患者的病情惡化。

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."

“我們發現,含有細菌較多的腫瘤含有的真菌也較多,而含有細菌較少的腫瘤含有的真菌也較少”,斯特勞斯曼說道?!澳壳拔覀冎荒芡茰y,有些腫瘤對微生物的存在比較苛刻,而有些腫瘤則比較寬容”。

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.

就像細菌一樣,其中某些真菌似乎在操縱免疫系統以利于腫瘤??茖W家發現球形馬拉色菌會加速一種胰腺癌的發展。根據施特勞斯曼和他在加州大學圣地亞哥分校的同事們的研究,他們在乳腺癌患者身上也發現了同樣的真菌,這些患者的總生存時間往往較短。也有研究發現,胰腺癌中存在的某些真菌會劫持部分免疫系統,以促進腫瘤生長。

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?

雖然這些發現進展很快,但關于腫瘤與腫瘤內微生物之間的關系,仍然存在許多問題。微生物從一開始就在腫瘤的發展中發揮作用嗎?還是只是機會性的居民,當它們找到癌癥家園時,適應并保護他們的家園?能否利用這種微生物群落來幫助我們對抗癌癥?

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.

在未來的幾年里,研究腫瘤內的微生物可能與研究癌細胞一樣重要,從而實現早期診斷,甚至發明新式療法,但這項工作才剛剛開始。