Specific Immune Cells Play An Essential Role In Tumor Growth
UCSF researchers have discovered that blocking the function of a certain type of immune cell halts pancreatic islet tumor growth in mice. The finding proves, they say, that specific immune cells can play a critical role in the formation and subsequent growth of cancer.
The immune cell in question, the mast cell, plays a key role in inflammation by releasing histamine and other chemicals in the body. More commonly associated with asthma, eczema and allergy, mast cells also appear at the edges of invasive tumors in numerous types of cancer in humans. The researchers discovered that the accumulation of mast cells is required for blood vessel formation (angiogenesis) in tumors in mice. Blocking mast cell function completely shut down the ability of the tumor to commandeer the nutrients it needs for growth.
The researchers discovered this by administering a common anti-asthma/anti-allergy medication, cromolyn, at the site of the tumor. The medication triggered tumor shrinkage and regression in mice with pre-existing pancreatic islet tumors.
Cromolyn is currently designed to be delivered topically or by inhalation and is not optimized for whole body delivery in humans. However, the researchers stress that now that the importance of mast cells has been demonstrated, new mast cell-blocking drugs like cromolyn could be specifically designed for appropriate systemic delivery.
The study results will be reported on September 30th in an advance online publication by the journal Nature Medicine. The journal will also publish the findings in an upcoming print edition.
"This study provides a potential new target for stopping cancer progression that scientists and drug makers should further explore," said Gerard Evan, the Gerson and Barbara Bass Baker Distinguished Professor of Cancer Biology at UCSF, and co-leader of the Cell Cycling and Signaling Program at the UCSF Comprehensive Cancer Center. "In addition, a new design of cromolyn administration should be useful in stopping the expansion of pancreatic and other cancers in humans."
An association between inflammation and cancer has long been recognized, though it remains unclear to what extent inflammation is a cause or consequence of tumor growth. Recently, it has become clear, says Evan, that some oncogenes (a class of genes that stimulate normal cell growth but when mutated drive cancer) may be responsible for inducing inflammation at the tumor site.
To test this idea, the UCSF lab group explored how Myc, an oncogene mutated in the majority of human cancers, drives pancreatic islet cancer (tumors of the beta cells that make insulin in the pancreas). In a previous study, the researchers showed that acute activation of the Myc oncogene triggered the rapid onset of pancreatic tumor angiogenesis and restructuring of the connective framework surrounding and nurturing the tumor.
The current study involved inserting a "switchable" form of Myc into beta cells and activating the oncogene.
"By observing and documenting the formation of cancer in the body from its earliest stages using switchable systems, we were able to identify each sequential step along the way, as well as the particular role different genes and cell types play in that process," said lead author Laura Soucek, PhD, postdoctoral scholar at the UCSF Cancer Research Institute and member of Gerard Evan's lab.
The researchers found that the activation of the Myc oncogene engaged a broad array of inflammatory signals that in turn recruited immune cells to the tumor. Most notable was an influx of mast cells to the tumor within a few hours of Myc activation.
"Myc activation in pancreatic beta cells triggered the recruitment of inflammatory cells, including mast cells, macrophages and neutrophils to the site," explained Soucek. "But the mast cells were the only inflammatory cells present at an early stage of activation, leading us to further explore whether this particular immune cell causally contributed to tumor growth."
To validate independently the role of mast cells in tumor growth, the researchers used both genetic and pharmacological (drug) approaches to block mast cell production. For the genetic study, they used a mutant mouse that lacks any mast cells and compared it to normal mouse "controls." Following Myc activation, control mice rapidly developed pancreatic islet tumors while the mice with no mast cells showed no tumor growth.
The researchers then asked whether the anti-allergy medication cromolyn, which blocks the release of histamine and other chemicals from mast cells, would also block islet tumor formation. Remarkably, as noted above, cromolyn treatment not only halted tumor growth, but also triggered shrinking of established tumors.
"The cromolyn induced blockade of mast cells triggered blood vessel collapse in established tumors, pinning a direct role on mast cells in tumor angiogenesis and vascular maintenance," said Soucek. "The collapse confirmed the essential role that mast cells have in blood vessel formation following Myc activation."
According to the researchers, recruitment of mast cells exemplifies how the Myc oncogene directly instructs tissue remodeling, angiogenesis and inflammation. The study findings demonstrate that the mutated Myc oncogene maintains its own complex inflammatory program and can alone trigger the inflammation typically associated with cancers.
"Our study underscores that cancer growth is not only about the mutated cancer cells themselves, but also how such wayward cells foster their own growth by instructing, informing and hijacking the tissues surrounding them," added Evan.
The UCSF study was funded by the National Institutes of Health (NIH), the National Cancer Institute and the Juvenile Diabetes Research Foundation.