Tumors as Invasive Species

“Cancer cells act as invasive species by their very nature,” said Sarah R. Amend, PhD, of the Johns Hopkins School of Medicine in Baltimore, Maryland. “Cancer cells are defined by high proliferation rates and resistance to programmed cell death.”

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Unlike ecological invasions, cancers arise from a native host organ, such as breast epithelia, and then invade the previously healthy local extratumoral ecosystem, she said.

Tumors reengineer the healthy cellular ecosystem to prepare the way for their own growth and spread, researchers now believe.

Dr Isacke’s team found that tumor cell-secreted Wnt7a, a cell-development signaling protein, can activate fibroblasts in the tumor microenvironment stroma, promoting tumor aggressiveness, for example. In other words, tumors can remodel their microenvironment to be more “permissive” to tumor growth, they believe.

The Tumor “Swamp”

Dr Amend likens the process of microenvironment exploitation to that of transforming a healthy meadow or forest ecosystem into a swamp.

“The cancer swamp is generated through a process of autoeutrophication,” Dr Amend explained. “It is self-instigated and self-maintained by the invasive and highly proliferative cancer cells. This acyclic nutrient cycling generates a hypoxic (low oxygen), acidic (high pH), and nutrient poor habitat: the cancer swamp.”

The severity of the ecological changes in a cancer swamp might well predict the aggressiveness of metastatic spread.

Central to the ecosystem model of tumor biology is nutrient cycling, the process whereby organisms acquire and use nutrients, and then excrete them back into the nutrient pool, where the process repeats, explained Dr Amend.

“In a healthy ecosystem, such as a lake or a healthy organ, nutrient cycles are self-regulating, with nutrients-in equaling nutrients-out. This balance, and the cooperation of individuals in an ecosystem, is essential for ecosystem health. When some external force acts upon a healthy balanced ecosystem, it can result in acyclic nutrient cycling: nutrients-in will no longer equal nutrients-out.” 

Proliferative tumor cells act as invasive species with rapid growth and proliferation, “disrupting the tightly regulated nutrient cycling of the host organ,” she said. They rapidly deplete the local nutrient pool.

“In our model, highly proliferative cancer cells pollute the healthy organ ecosystem, rapidly outstripping the native vasculature, thus overwhelming the incoming tributaries that supply nutrients as well as the outgoing distuaries that carry away cellular waste,” Dr Amend said.

The result is a hypoxic, acidic, and nutrient poor cancer swamp, encroaching upon the healthy, oxygenated, pH-neutral, and nutrient-rich healthy organ ecosystem, she said. “It is clear that breast tumors, along with all other solid tumors, generate a cancer swamp even before the disease is clinically detectable.”

Another factor in tumor ecology is the still-poorly-understood host microbiome.

“I think of the microbiome as ‘dark matter’ of human health,” Dr Verbridge said. “An appreciable fraction of our body weight is bacterial. We’re in the midst of a revolution of understanding how the microbiome can tune the immune system toward heart disease or cancer.”

Dr. Verbridge’s lab is studying how bacterial populations in host tissue can tune stress responses in tumor evolution. A particular local population of bacteria might affect tumors’ ability to adapt to low pH or oxygen, or the presence of cytotoxic drugs, for example. By experimentally controlling cells’ interactions and microenvironments, they hope to isolate and understand the roles of such variables in tumor progression.

“We’re looking specifically at populations of bacteria present in breast tissue,” Dr Verbridge said. “That’s fairly novel. A lot of researchers are focused on the gut microbiome right now.”

His team is looking at bacterial factors secreted into breast tissue, and how these secreted proteins can affect survival in tumor and normal cells.

“Then we’re stressing the normal and tumor cells, exposing them to low pH and low oxygen, and to chemo drugs,” he added.

As findings from such experiments accumulate, it should become possible to identify local bacterial populations and communities that promote tumor cell growth and adaptation to treatment. “Maybe having the correct bacteria might block or promote tumor growth,” Dr Verbridge hopes.