The Surprising Connection Between Healthy Human Embryos and Treatment-Resistant Cancer

The Surprising Connection Between Healthy Human Embryos and Treatment-Resistant Cancer

A retrovirus illustration.

(© fotoliaxrender/Fotolia)


Even with groundbreaking advances in cancer treatment and research over the past two centuries, the problem remains that some cancer does not respond to treatment. A subset of patients experience recurrence or metastasis, even when the original tumor is detected at an early stage.

"Why do some tumors evolve into metastatic disease that is then capable of spreading, while other tumors do not?"

Moreover, doctors are not able to tell in advance which patients will respond to treatment and which will not. This means that many patients endure conventional cancer therapies, like countless rounds of chemo and radiation, that do not ultimately increase their likelihood of survival.

Researchers are beginning to understand why some tumors respond to treatment and others do not. The answer appears to lie in the strange connection between human life at its earliest stages — and retroviruses. A retrovirus is different than a regular virus in that its RNA is reverse-transcribed into DNA, which makes it possible for its genetic material to be integrated into a host's genome, and passed on to subsequent generations.

Researchers have shown that reactivation of retroviral sequences is associated with the survival of developing embryos. Certain retroviral sequences must be expressed around the 8-cell stage for successful embryonic development. Active expression of retroviral sequences is required for proper functioning of human embryonic stem cells. These sequences must then shut down at the later state, or the embryo will fail to develop. And here's where things get really interesting: If specific stem cell-associated retroviral sequences become activated again later in life, they seem to play a role in some cancers becoming lethal.

"Eight to 10 million years ago, at the time when we became primates, the population was infected with a virus."

While some retroviral sequences in our genome contribute to the restriction of viral infection and appear to have contributed to the development of the placenta, they can also, if expressed at the wrong time, drive the development of cancer stem cells. Described as the "beating hearts" of treatment-resistant tumors, cancer stem cells are robust and long-living, and they can maintain the ability to proliferate indefinitely.

This apparent connection has inspired Gennadi V. Glinsky, a research scientist at the Institute of Engineering in Medicine at UC San Diego, to find better ways to diagnose and treat metastatic cancer. Glinsky specializes in the development of new technologies, methods, and system integration approaches for personalized genomics-guided prevention and precision therapy of cancer and other common human disorders. We spoke with him about his work and the exciting possibilities it may open up for cancer patients. This interview has been edited and condensed for clarity.

What key questions have driven your research in this area?

I was thinking for years that the major mysteries are: Why do some tumors evolve into metastatic disease that is then capable of spreading, while other tumors do not? What explains some cancer cells' ability to get into the blood or lymph nodes and be able to survive in this very foreign, hostile environment of circulatory channels, and then be able to escape and take root elsewhere in the body?

"If you detect conventional cancer early, and treat it early, it will be cured. But with cancer involving stem cells, even if you diagnose it early, it will come back."

When we were able to do genomic analysis on enough early stage cancers, we arrived at an alternative concept of cancer that starts in the stem cells. Stem cells exist throughout our bodies, so in the case of cancer starting in stem cells you will have metastatic properties … because that's what stem cells do. They can travel throughout the body, they can make any other type of cell or resemble them.

So there are basically two types of cancer: conventional non-stem cell cancer and stem cell-like cancer. If you detect conventional cancer early, and treat it early, it will be cured. But with cancer involving stem cells, even if you diagnose it early, it will come back.

What causes some cancer to originate in stem cells?

Cancer stem cells possess stemness [or the ability to self-renew, differentiate, and survive chemical and physical insults]. Stemness is driven by the reactivation of retroviral sequences that have been integrated into the human genome.

Tell me about these retroviral sequences.

Eight to 10 million years ago, at the time when we became primates, the population was infected with a virus. Part of the population survived and the virus was integrated into our primate ancestors' genome. These are known as human endogenous retroviruses, or HERVs. The DNA of the host cells became carriers of these retroviral sequences, and whenever the host cells multiply, they carry the sequences in them and pass them on to future generations.

This pattern of infection and integration of retroviral sequences has happened thousands of times during our evolutionary history. As a result, eight percent of the human genome is derived from these different retroviral sequences.

We've found that some HERVs are expressed in some cancers. For example, 10-15 percent of prostate cancer is stem cell-like. But at first it was not understood what this HERV expression meant.

Gennadi V. Glinsky, a research scientist at the Institute of Engineering in Medicine at UC San Diego.

(Courtesy)

How have you endeavored to solve this in your lab?

We were trying to track down metastatic prostate cancer. We found a molecular signature of prostate cancer that made the prostate tumors look like stem cells. And those were the ones likely to fail cancer therapy. Then we applied this signature to other types of cancers and we found that uniformly, tumors that exhibit stemness fail therapy.

Then in 2014, several breakthrough papers came out that linked the activation of the retroviral sequences in human embryonic stem cells and in human embryo development. When I read these papers, it occurred to me that if these retroviral sequences are required for pluripotency in human embryonic stem cells, they must be involved in stem cell-resembling human cancer that's likely to fail therapy.

What was one of the biggest aha moments in your cancer research?

Several major labs around the U.S. took advantage of The Cancer Genome Anatomy Project, which made it possible to have access to about 12,000 individual human tumors across a spectrum of 30 or so cancer types. This is the largest set of tumors that's ever been made available in a comprehensive and state of the art way. So we now know all there is to know about the genetics of these tumors, including the long-term clinical outcome.

"When we cross-referenced these 10,713 human cancer survival genes to see how many are part of the retroviral network in human cells, we found that the answer was 97 percent!"

These labs identified 10,713 human genes that were associated with the likelihood of patients surviving or dying after [cancer] treatment. I call them the human cancer survival genes, and there are two classes of them: one whose high expression in tumors correlates with an increased likelihood of survival and one whose high expression in tumors correlates with a decreased likelihood of survival.

When we cross-referenced these 10,713 human cancer survival genes to see how many are part of the retroviral network in human cells, we found that the answer was 97 percent!

How will all of this new knowledge change how cancer is treated?

To make cancer stem cells vulnerable to treatment, you need to interfere with stemness and the stemness network. And to do this, you would need to identify the retroviral component of the network, and interfere with this component therapeutically.

The real breakthrough will come when we start to treat these early stage stem cell-like cancers with stem cell-targeting therapy that we are trying to develop. And with our ability to detect the retroviral genome activation, we will be able to detect stem cell-like cancer very early on.

How far away are we from being able to apply this information clinically?

We have two molecule [treatment] candidates. We know that they efficiently interfere with the stemness program in the cells. The road to clinical trials is typically a long one, but since we're clear about our targets, it's a shorter road. We would like to say it's two to three years until we can start a human trial.

Keep Reading Keep Reading
Kristen Hovet
Kristen is a science journalist, specializing in the areas of psychology, medical innovations, and the intersection of sociology and culture. Her focus is in making science information accessible and meaningful to a wide variety of individuals. Originally from North Dakota, Kristen is currently based in Vancouver, Canada. She received her degree in English from Simon Fraser University. A lifelong learner with many interests, she has completed certificates in epigenetics, personalized medicine, genetics and evolution, and physiology. Kristen hosts the Humans of Earth podcast.
Man Who Got the First Fecal Transplant to Cure Melanoma Shares His Experience

Jamie Rettinger with his now fiance Amie Purnel-Davis, who helped him through the clinical trial.

Photo courtesy of Jamie Rettinger

Jamie Rettinger was still in his thirties when he first noticed a tiny streak of brown running through the thumbnail of his right hand. It slowly grew wider and the skin underneath began to deteriorate before he went to a local dermatologist in 2013. The doctor thought it was a wart and tried scooping it out, treating the affected area for three years before finally removing the nail bed and sending it off to a pathology lab for analysis.

"I have some bad news for you; what we removed was a five-millimeter melanoma, a cancerous tumor that often spreads," Jamie recalls being told on his return visit. "I'd never heard of cancer coming through a thumbnail," he says. None of his doctors had ever mentioned it either. "I just thought I was being treated for a wart." But nothing was healing and it continued to bleed.

A few months later a surgeon amputated the top half of his thumb. Lymph node biopsy tested negative for spread of the cancer and when the bandages finally came off, Jamie thought his medical issues were resolved.

Keep Reading Keep Reading
Bob Roehr
Bob Roehr is a biomedical journalist based in Washington, DC. Over the last twenty-five years he has written extensively for The BMJ, Scientific American, PNAS, Proto, and myriad other publications. He is primarily interested in HIV, infectious disease, immunology, and how growing knowledge of the microbiome is changing our understanding of health and disease. He is working on a book about the ways the body can at least partially control HIV and how that has influenced (or not) the search for a treatment and cure.
Scientists want the salamander's secret: how they regenerate tissue

All organisms can repair damaged tissue, but none do it better than salamanders and newts. A surprising area of science could tell us how they manage this feat - and perhaps even help us develop a similar ability.

Adobe Stock

All organisms have the capacity to repair or regenerate tissue damage. None can do it better than salamanders or newts, which can regenerate an entire severed limb.

That feat has amazed and delighted man from the dawn of time and led to endless attempts to understand how it happens – and whether we can control it for our own purposes. An exciting new clue toward that understanding has come from a surprising source: research on the decline of cells, called cellular senescence.

Keep Reading Keep Reading
Bob Roehr
Bob Roehr is a biomedical journalist based in Washington, DC. Over the last twenty-five years he has written extensively for The BMJ, Scientific American, PNAS, Proto, and myriad other publications. He is primarily interested in HIV, infectious disease, immunology, and how growing knowledge of the microbiome is changing our understanding of health and disease. He is working on a book about the ways the body can at least partially control HIV and how that has influenced (or not) the search for a treatment and cure.