Bacteria, Infection, Inflammation… Cancer?
Guess what? Urine’s not sterile! This may be bad news for people like TV survival expert Bear Grylls, who often resorts to drinking his own urine to stay hydrated in the wilderness. But it’s startling and exciting news to scientists, who for years believed that if bacteria were present in urine, it must signal the presence of infection.
It turns out that you can have bacteria in your urine and not have an infection that leads to symptoms that need to be treated. So… what does this have to do with prostate cancer?
Briefly, urine gets from Point A, your bladder, to Point B, the tip of your penis and on to the outside world, through a pipeline called the urethra. The pipeline runs through a tunnel: your prostate. It is possible that there’s some percolation going on: that, like coffee through a small filter, some urine seeps into the prostate on its journey south. It is also possible that, like ticks on a dog, some uninvited guests (bacteria) come along for the ride.
So we have a potential perpetrator at the scene of the crime. Now all we need is the smoking gun: proof that, as some scientists suspect, bacteria indeed hitches a ride into the prostate via the urine, loiters there indefinitely, incites chronic, low-grade inflammation, and over time this causes cancer.
This wouldn’t be the first time this particular chain of events has happened in the body. When it comes to causing cancer, as they say, it’s not bacteria’s first rodeo.
“If you look at the forensic crime scene of other cancers, such as stomach cancer caused by H. pylori bacteria, we have all the same players we see in prostate cancer,” says Johns Hopkins scientist Karen Sfanos, Ph.D. With funding from the Prostate Cancer Foundation, she is looking hard for that smoking gun. “It’s not just the presence of the bacteria, but the fact that the bacterium gets into the stomach, causes inflammation and ulcers, causes gastric atrophy (death of tissue), and that’s the risk factor for cancer. We know there are cancers that are linked to infection, and those infection-linked cancers almost always have inflammation as a co-factor.”
Sfanos and her colleague, Johns Hopkins pathologist Angelo De Marzo, M.D., Ph.D., have seen plenty of inflammation in prostate tissue. “We see prostates at autopsy, we see specimens after prostate cancer surgery, we see tissue taken from biopsy and during treatment for benign diseases,” she continues. “And we often see the same things that we see in H.pylori-induced stomach cancer: inflammation and atrophy.”
Similarly, “Chronic inflammation is very well known in liver cancer,” says De Marzo. “People who have hepatitis B or C, when they don’t get rid of the virus, they have chronic inflammation and it ends up damaging the liver. The liver tissue regenerates in the setting of inflammatory cells, and ultimately this can lead to cancer.”
PIA is proliferative inflammatory atrophy; if you have ever had a prostate biopsy, the pathologist reading your slides may have seen this as one of the pathologic findings under the microscope. It’s not cancer, but it keeps bad company;
PIA is often seen right beside areas of prostate cancer. De Marzo is a pioneer in the study of PIA, and for years he has argued that these tiny bits of dried-up, shrunken cells are precursors to cancer. Weirdly, even though these cells look withered, they are dividing like crazy – not quite cancer-crazy, but definitely faster than normal cells divide.
And right in the thick of it, throughout this complex mess of PIA, cancer cells, PIN (another set of weird-looking cells more closely linked to prostate cancer and a likely intermediate step between PIA and cancer), and normal cells, is inflammation.
Inflammation in the prostate is extremely common. “We see way too many inflammatory cells in prostate tissue,” says De Marzo. In one study, De Marzo, Scott Lucia, a pathologist at the University of Colorado, Johns Hopkins epidemiologist Elizabeth Platz, and colleagues looked at prostate tissue from 400 men with and without prostate cancer. “The likelihood of having cancer if there was inflammation was 1.6 times higher overall, and 2.2 times higher for high-grade cancer, versus if inflammation was not present,” says De Marzo. “It seems that the more inflammation, the higher the odds of having prostate cancer, and of having high-grade cancer.”
Normally, he explains, there are “a few scattered inflammatory cells, kind of like sentinels – one posted here, one posted there. But with inflammation, there’s a much larger influx. When they’re in a group, like teenagers in a group, disasters can happen. They think they’re fighting something, and maybe they are.”
Inflammation is two-faced. Its actual purpose in the body is to be a good guy: to fight off infection, defend against enemy invaders, and kill cancer. And yet, here it is, also maybe causing cancer. Is it a chicken-egg question – as in, which came first, the inflammation or the cancer? The answer may very well be an infuriating “Yes.” Says De Marzo: “We think it is a double-edged sword. In some of the same families of cells that we see, inflammation can simultaneously be driving the tumor, and also trying to kill it.”
There are lots of different types of inflammatory cells – T cells, B cells, macrophages, neutrophils, mast cells. “We’re just beginning to characterize the different types,” says De Marzo.
With new technology, based on the revolution in “next-generation DNA sequencing,” Sfanos is able to take a region of tissue or a urine sample, extract the DNA, and sequence regions of the DNA to identify of all the bacteria present in it. “I’ve been studying this since I was a grad student,” she says. And now, “there’s this whole brand new concept: now that we know that urine is not completely sterile, we can focus on determining if there is a microbiome of the prostatic urethra. There is potentially an important source of bacteria sitting right there.”
Remember the pipeline? That stretch through the tunnel, the place where the urethra passes through the prostate, has its own microclimate. Just as the earth has its own ecosystems – tundra, tropical rainforests, grasslands – your body has them, too: dozens of them, picky little cliques of bacteria that only thrive in one particular spot. For example: You get acne on your face, but you never develop a zit on your hand. There may be something in that very particular spot, the prostatic urethra, that’s conducive to cancer.
The problem is, nobody knows what’s normal. What’s supposed to be in the prostate? Is it okay for some bacteria to be in there, but not others? “It could be that there’s a shift in the flora that might make the prostate more susceptible to infections that drive cancer,” says Sfanos. Like a homicide detective trying to identify a suspect, she is “profiling” the bacteria in urine samples from men with and without prostate cancer. “We are finding a very distinct flora in men that’s different from what’s been reported as normal flora in the urinary tract of women. So we’re trying to understand as a first point, what is a normal urinary flora in a man, because that’s not even been described before.”
It may be that the bacterial culprit is something that everyone has, but something tips the balance and it starts to do bad things. Many of us have H. pylori in the gut, for example; and for the vast majority of us, it doesn’t cause any harm. But for some of us, it does.
There’s another microclimate, too – a tiny ecosystem of bacteria – in the foreskin. “Every region of your body has its own unique bacteria,” says oncologist Jonathan Simons, M.D., CEO of the Prostate Cancer Foundation. “It’s like topsoil, and only specific plants grow in the exact topsoil of very distinct regions. These regions are all being mapped right now, so we’re just starting to learn about what it is that would grow under the foreskin that might be permissive to creating inflammation that, in turn, might make it easier for cancer to develop.”
Prostate cancer is more common in uncircumcised men. Evidence from studies by De Marzo, Sfanos, and Elizabeth Platz and others including Washington University epidemiologist Siobhan Suttcliffe, Ph.D., suggests that sexually transmitted diseases may somehow jump-start the initial “inflammatory event,” and then the inflammation may just keep on happening after the STD has cleared.
“Even just one infection may be enough to start chronic inflammation,” says Sfanos.
Circumcision – the surgical removal of the flap of skin at the tip of the penis, usually done a few days after birth – helps protect against sexually transmitted diseases. Several studies from around the world have shown men who are circumcised are less likely to get HIV, HPV (the virus that causes genital warts and cervical cancer), syphilis, genital herpes, and penile cancer.
Circumcision also lowers your risk of getting prostate cancer. So what is it about the foreskin, that small flap of skin, that raises the cancer risk? It’s not the flap itself; it’s simply that the extra layer of skin provides a potential breeding ground for bacteria and viruses. Circumcision seems to be protective in that it takes away one extra shelter for bacteria.
…So Does Safe Sex
And that brings us to the subject of sex in general. Men who have not had a history of STDs and who ejaculate more frequently have a slightly lower risk of getting prostate cancer; the thought here is that this “cleans house,” and keeps semen (the prostate’s official function is to contribute part of the fluid that makes up semen) moving through the male plumbing, taking with it any bacteria and other potential cancer causing chemicals that it might pick up when passing through the prostate. So that’s good.
However, notes Sfanos, “some men can be carriers of the microorganisms that cause sexually transmitted infections that are just hanging out in the urinary tract. A man could carry microorganisms in his urinary tract that are capable of inducing a decent amount of inflammation in his prostate, but causes no symptoms of a prostate infection. The more sexual partners you have, the more this might make your risk go up of getting an infection that will cause inflammation that will one day lead to prostate cancer.” So, says Sfanos, one clear way to lower your risk of contracting an STD is to practice “safe sex.”
And Then There’s the Barrier
The epithelium is the lining of the prostate. It is a protective barrier. Imagine, for a minute, that it’s a cold day, but you’re warm because you’re wearing long johns under your clothes. But if that long underwear were ripped, or the fabric became very thin and weak, it wouldn’t keep you as toasty. De Marzo suspects that a breach in the armor might allow infection to enter the prostate. “If there’s a bunch of bacteria hanging out in the urethra that can “reflux” into the prostate, that are normally kept at bay, and now somehow the barrier is breached, a bacterium that normally would never cause a problem could get in there and predispose the prostate to cancer.”
What might disrupt that barrier? “Charred meats.” He continues: “Charred meats can injure the prostate in rodents.”
When meat is cooked at a high temperature – when a steak, burger, hot dog, or even a piece of cooked fish gets those grill marks that most of us really like to see – it produces a bad ingredient called PhIP. PhIP, a short name for a long chemical compound, is a “pro-carcinogen,” a chemical that turns into something that can attack and mutate your DNA. PhIP is known to cause prostate (and breast, and colon) cancer in rats.
A Johns Hopkins scientist named Bill Nelson, M.D., Ph.D., has been studying PhIP for years along with De Marzo and Sfanos. Together, they found that chronic inflammation – in this case, caused by E.coli – plus a diet heavy in charred food led to an increase in the development and progression of cancer in the skin and digestive tract in rats. Rats that had both E.coli and PhIP got more precancerous lesions in their prostates, too, and they might have developed even more problems – except they died sooner. When the scientists inoculated PhIP-fed rats with E.coli in the prostate, “the animals developed acute and chronic prostate inflammation out of proportion to that seen with PhIP ingestion alone,” and had more prostate neoplasms (new, abnormal cell growth, particularly of PIN) as well as invasive cancers at other sites including the intestines and skin. The scientists concluded that prostate infection and dietary carcinogens might work together in an unfortunate way to “promote chronic prostate inflammation and prostate cancers.”
There is a light in this particular tunnel: Veggies. When the scientists fed rats tomatoes and broccoli along with PhIP, the rats lived longer and had fewer prostate neoplasms, intestinal cancers, and skin cancers than the rats that just ate the PhIP. Don’t be that guy who hates veggies unless they’re deep-fried and dipped in ranch. Learn to love broccoli. Really.
So, if the barrier is broken – if the gate is stormed, like a medieval castle – can it be fixed? “That’s one of the great questions right now in prostate cancer research,” says Simons. “Is it fundamentally a breakdown caused by diet that makes the microbiome more inflammatory? And is it possible to cool off the inflammation in the prostate?” The PCF has funded $2 million of research on a randomized placebo-controlled trial – the only one of its kind – to see whether drinking the ultimate green smoothie, eight fluid ounces of broccoli a day, can reduce prostate inflammation, as measured in the urine. Tomatoes, green tea, and other foods have anti-inflammatory properties, as well. (Note: Losing weight is another excellent way to remove some of the inflammatory fuel within the prostate.)
“If we could figure out whether inflammation is driving the cancer,” says De Marzo, “if it’s causing 20, 30, even 50 percent of prostate cancer, maybe just by reducing inflammation, we could make a huge difference.”