MSK scientists shed new light on a tumor's earliest moments

Scientists at Memorial Sloan Kettering Cancer Center (MSK) and their colleagues are shedding new light on a tumor's earliest moments - revealing how lung cells with cancer-causing mutations recruit accomplices from healthy surrounding tissue to pave the way for a tumor to develop.

The team's findings show that when this communication with surrounding cells is disrupted, tumors fail to grow.

Cancer hijacks the body's healing response

Normally, when a lung tissue is damaged, specialized stem cells enter a regenerative state where they become flexible so they can replace the damaged cells. Then, once the injury is repaired, they go back to normal.

A three-way communication network

What they discovered is a three-step process:

• First, the mutant cells enter regenerative states and produce high levels of a protein called amphiregulin (AREG). "This is a distress signal, which is received by nearby healthy cells," Dr. Lee says.
• Second, connective tissue cells called fibroblasts receive this signal and act as if they are responding to an injury. The fibroblasts become "fibrotic," producing a fibrous scaffold around the tumors, as they would during normal wound healing.
• Third, the activated fibroblasts help tumor cells grow and also send their own signals that reshape the local immune response. Macrophages expand at the site and actually suppress the immune response, rather than attacking the mutant cells. It happens because these reprogrammed cells call in the wrong backup - instead of attracting cancer-fighting immune cells, they recruit cells including neutrophils and regulatory T cells, whose normal role is to quiet things down and prevent the immune system from overreacting and damaging the body's own tissues.

The result is a self-reinforcing loop, Cardoso says. The remodeled environment helps tumor cells maintain their regenerative state, while the tumor cells continue to send out their distress call, which reshapes the tissue around them. Together, these conditions create a conducive environment for a tumor to grow and progress.

The critical role of fibroblasts

A key insight in the study came from Cardoso's analysis of the data, Dr. Lee says.

Blocking injury signals can prevent tumor formation

The researchers then asked a crucial question: What happens if you disrupt this communication network between cancer-causing cells and the normal cells in their neighborhood?

From mouse models to human cells

Findings in laboratory models, however, don't always hold true in actual patients. So the team took steps to test the applicability of their findings.

When they analyzed tissue samples from patients with early-stage lung adenocarcinoma, they found the same key players positioned close together: cancer cells producing high levels of AREG and adjacent fibrotic fibroblasts.

But patient tissue samples can only provide a single snapshot in time - they can't show the sequence of events as cancer develops.

A general mechanism across cancer types?

Opening a window for early intervention

They might be especially relevant for people at high risk of developing lung cancer - such as long-term smokers or those with genetic predispositions - who might unknowingly harbor precancerous cells with oncogenic mutations.

Understanding cancer's ecosystem

Overall, the work exemplifies an important shift in how we think about cancer's origins, Dr. Lee says.

"The key message we'd really like to deliver is: When tumors first emerge, they hijack the regenerative program, and they interact with healthy cells to generate a microenvironment supporting the cancer," she says. "This determines whether these tumor cells sustain and progress - and it happens at a very, very early stage."

Source:

Memorial Sloan Kettering Cancer Center

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