Crist found that if she gave cancer cells “emergency provisions” by boosting the level of an antioxidant enzyme called catalase, they could grow new tumors in skeletal muscle. But when the team routed catalase-amped tumor cells to the lung, the extra catalase inhibited their growth and reduced lung metastases. Turning their antioxidant capacity up even further killed the lung mets off.
“So what does that tell us? It tells us there’s an optimal level of oxidation and reduction [antioxidation] that a tumor cell needs and it’s tuned to the tissue it’s in,” Ghajar said.
He and Crist hadn’t just revealed a tumor-suppressing process in skeletal muscle, they had revealed an inner truth about tumor cells and how they relate to their surroundings. Ghajar and his team are now working to figure out how they can exploit this vulnerability to permanently press snooze on dormant tumor cells (or even kill them off) and prevent stage 4 disease.
While there are several therapeutic avenues his team is exploring, Ghajar favors an approach that could work in every tissue that harbors dormant tumor cells. His team turned to the immune system.
The immune system: a mobile microenvironment
Our immune system is an incredibly complex interconnected set of cells and molecules that collaborate on one goal: keep disease at bay. Disease mostly means infection, but the immune system can also defend against cancer.
Because a pathogen or tumor could strike anywhere in the body, immune cells are highly mobile. They ride along blood vessels and squeeze into tissues to heed the call of injured cells or to hunt for hidden dangers. An arriving company of immune cells can change a tissue’s microenvironment.
Mice with defective immune systems develop tumors at earlier ages than mice with normal immune systems. The tumors that grow in spite of an immune system are often less able to trigger immune activity, a hint that they succeeded by evolving ways to fly under the immune system’s radar. And when researchers look at the cellular components of tumors, the presence of certain immune cells can correlate with a better prognosis, suggesting that these cells are working to restrain the tumor. (Unfortunately, some cancers find ways to convince immune cells to collaborate with them and enhance tumor growth and spread.)
But immune cells are unlikely to act when there’s just one mutated or cancerous cell, said Dr. Shivani Srivastava, a Hutch researcher who studies how to improve cancer immunotherapies. Immune cells like T cells are most effective when they’re flagged down and directed where to go; a single cell, cancerous or not, is unlikely to send out the necessary SOS. So, while our immune system can help us once we have a tumor already, it’s probably doesn’t play much of a role in keeping us from developing them in the first place.
Srivastava studies immunotherapies based on a type of immune cell known as a T cell. T cells carry a specialized molecule on their surface, called a T-cell receptor, that helps them seek out and kill off diseased cells. Immunotherapies in which T cells have been genetically engineered to find cancer cells have been approved for certain blood cancers, but scientists are hoping to expand their scope to other cancer types.
Ghajar hoped that the immune system could hold similar hope for patients with metastasized breast cancer. Dr. Erica Goddard, a postdoctoral fellow in Ghajar’s lab, teamed up with Srivastava and Hutch immunotherapy expert Dr. Stan Riddell to study the problem. A single dormant breast tumor cell seems like it would be no match for a deadly T cell. It doesn’t have to be, it turns out.
“There’s a very simple explanation for how [dormant tumor cells] evade immunity, which is that they’re rare,” Ghajar said.
It’s a numbers game: We have more than 30 billion cells in our bodies that a handful of cancer-attuned T cells must hunt through.
“It’s like trying to win the dormancy lottery again and again,” Ghajar said. “So how do you tilt things in your favor?”
With numbers. Goddard and Ghajar, with Riddell’s team, showed in mouse studies that a host of engineered T cells change the odds from slim-to-none to pretty fantastic.
There’s still work to do: T cells need a specific target to home in on. Ghajar has worked with Hutch epidemiologist Dr. Chris Li and an expanding team to recruit women with early-stage breast cancer — who likely have cancer cells slumbering in their bone marrow — to donate bone marrow samples. The scientists can screen these samples for dormant tumor cells and characteristic mutations that T cells could target. The team hopes this work reveals targets they can use to develop an immunotherapy that prevents metastatic breast cancer.
The project is part of TRANCE, a multi-disciplinary, multi-center collaboration supported by a $25 million Department of Defense grant co-led by Ghajar and Li. The TRANCE consortium aims to develop strategies to kill or silence dormant tumor cells.
Context matters, but so does the mutation
When Beronja started studying how cells stopped cancer-causing mutations from actually causing cancer, he expected that to see mutated cells choosing a couple of obvious strategies. Self-sacrifice is one obvious way a mutated cell could defend its tissue against cancer. Cells can also take what amounts to a permanent time out, a phenomenon known as senescence.
But mutated skin stem cells chose a different option: they persisted, and persistently continued fulfilling their functions as skin cells. The strategy underscores how imperative it is that skin stem cells continue fulfilling their role as the source of skin tissue, Beronja said.
To continually maintain skin’s upper layers, skin stem must continually produce differentiated skin cells with specialized functions. But they must also renew themselves to maintain the stem cells that are the source of skin tissue. Skin stem cells have to strike just the right balance between renewing themselves and differentiating. Tip too far either way, and skin will eventually break down. Too much renewal, and skin tissue isn’t replaced. Too much differentiation drains the well of skin stem cells — and eventually, skin tissue won’t be replaced.
How cancer doesn’t happen – Part 2 & Latest News Update
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