ddn Cancer Research News Exclusive: Making progress with progenitors
CAMBRIDGE, United Kingdom—It's well known that the replication of damaged cells is the basis cancer, but some of the latest research from across the pond has revealed two new types of immature cells in mammary glands that might provide new answers as to what kinds of cells certain breast cancers begin life as.
A research team at Cancer Research UK's Cambridge Research Institute has published a study identifying at least two types of progenitors cells: estrogen positive progenitors, which have estrogen receptors, and estrogen negative progenitors, which do not. Progenitor cells, unlike stem cells, can only divide a certain number of times. Prior to this discovery, only one type of progenitor cells in mammary glands had been identified, a heterogeneous population that is associated with basal-like breast cancer.
"This exciting discovery reveals that mammary glands are much more complicated than scientists initially thought," Dr. John Stingl of the Mammary Stem Cell Biology Laboratory at Cancer Research UK's Cambridge Research Institute said in a press release. "Uncovering new types of 'mother' cells may explain why there are different types of breast cancer, and why young and older women tend to get different types. It could also provide new starting points for ways to diagnose and treat the disease in the future."
Stingl, author of the study which appears in Breast Cancer Research, says his introduction to these new cells began about 10 years ago. While analyzing normal breast tissue samples with flow cytometry, Stingl noticed the luminal progenitor compartment was not uniform across all samples, with some samples presenting "not one, but two coherent populations" of cells. Stingl "suspected something," he says, but it has taken a number of years "to figure out how to reproducibly subdivide these populations and to characterize them."
The new progenitor cell types could be linked to known types of breast cancer. Estrogen positive progenitor cells fare better in an environment with low estrogen and progesterone (such as the breast tissue of post-menopausal women), and luminal A and B—estrogen receptor positive tumors that account for 60 to 65 percent of all breast cancer—share genetic similarities with estrogen positive progenitor cells, according to Stingl. Estrogen negative progenitor cells present with a genetic fingerprint similar to that of basal-like breast cancer.
It's unknown whether one of the groups of progenitor cells is more cancer-prone than the other, Stingl says.
This new information, and other recent discoveries in oncology, is changing preconceptions as to what the main culprit might be in terms of cells with the potential or predisposition to become cancerous.
"The previous line of thought was that tumors originated in tissue stem cells because these cells were long-lived enough to accumulate all the genetic mutation necessary to make a normal cell malignant; however, Matt Smalley published a paper in Cell Stem Cell a couple of years ago demonstrating that basal-like breast cancer, at least in a mouse model of breast cancer, originates in estrogen receptor negative luminal progenitors, " explains Stingl. "This has shifted thinking of the field, and more people are now becoming convinced that breast tumors may have their origin in luminal progenitor cells rather than basal stem cells."
It must be pointed out, Stingl adds, that "this line of thinking is probably too simplistic" given the complexity of cancer. He notes that a recent Nature publication showed that "the luminal cell compartment (a cell compartment that we thought did not contain stem cells, but only progenitor cells and mature cells) does in fact contain a population of stem cells – so it seems that at least one (or possibly multiple) progenitor cell types do have stem cell properties, although we don't know which ones."
Determining the cell of origin in cancer "is a difficult thing," Stingl says, given that cancer is the result of multiple mutations. A presiding hypothesis is that the first several mutations might begin in a stem cell, mutations which are then passed on to more mature progenitor daughter cells, which themselves acquire more mutations and pass them on to their daughters, which may end up being the differentiated cells. Those cells, Stingl explains, "then acquire the final mutation that makes them fully malignant." So while
"the stem cell acquired the first genetic hit … the mature cells are the ones that propagate the tumor. Thus the cell of origin of cancer gets to be a bit fuzzy."
Moving forward, Stingl says he and his colleagues are "examining the cellular context of common breast cancer mutations," to determine if expression of cancer-causing genes have the same effects in different types of breast cells, or if they tend to present specifically in certain cell types. In addition, he says the team is also "reverse-engineering tumors on different normal cell backgrounds. "
"This research takes us right to the root of how breast cells develop. This fresh understanding could reveal new ways to block the development of cancer and tell us more about what happens when tumors become resistant to treatment," Dr. Julie Sharp, Cancer Research UK's senior science information manager, said in a press release. "Cancer Research UK is a major funder of breast cancer research in the UK. Our research has contributed to progress that means eight out of 10 women now survive breast cancer for more than five years, compared with five out of 10 women in the 1970s. But there's much more to do. Research like this will build on our understanding of breast cancer to bring forward the day when we can beat this disease."