At least two camps have formed in the “breast cancer stem cell” world.

One camp believes most cancers may come from stem cells—or stem-like progenitors—gone awry. A leading proponent is University of Michigan oncologist Max Wicha, who reports breast cancers can come from two kinds of breast stem cells gone awry.

Others agree cancers can be most virulent when reaching a stem cell-like state—but believe they may come from both stem cells and mature cells gone awry. One proponent there is MIT’s Robert Weinberg, who proposed in 2011—and earlier—that both differentiated and stem cells can go malignant.

Graph showing The increase in cancer stem cell papers since 1980, when there was one.The field is in a different place than it was in 2001, when a single paper was published with the phrase “cancer stem cell” in the abstract. In the 12 years since, that number leapt to 4,627—1,130 last year alone, according to Pubmed.

But settling the issue of cancer’s origins is key, Wicha tells Bioscience Technology. “The importance of this concept is more than theoretical, since it has potential implications for the development of cancer stem cell (CSC) targeting therapeutics.”

There is a hierarchy in normal cells. Every organ has a pocket of rare, immature, multi-potent, organ/tissue-specific stem cells. These can both replicate, and differentiate into less replicative progenitors, which ultimately differentiate into the non-replicative, mature cells. Most tissues/organs operate this way.

For decades it was noticed the most virulent cancers often resemble stem cells. They tend to be immature in phenotype, and both replicate and differentiate into mature cells—if often caricatures of those.

University of Toronto hematologist John Dick isolated the first cancer stem cell, the acute myeloid leukemia stem cell, in the 1990’s. Irv Weissman’s group at Stanford University is credited with, in 2001, igniting a firestorm of interest in cancer stem cells in solid cancers. “Perhaps the most important and useful property of stem cells is that of self-renewal,” Weissman’s group reported. “Through this property, striking parallels can be found between stem cells and cancer cells: tumours may often originate from the transformation of normal stem cells, similar signalling pathways may regulate self-renewal in stem cells and cancer cells, and cancer cells may include 'cancer stem cells' - rare cells with indefinite potential for self-renewal that drive tumorigenesis.” Weissman commonly cautions that, while initiating events may occur in stem cells, more key cancer-causing events can occur in more differentiated progenitors of those affected stem cells.

Since then, Weissman’s paper has been cited more than 5,639 times, and cancer stem cells have been reported in breast, brain, colon—and more.

A few years after Weissman’s paper, Weinberg found that stem-cell like tumors can also derive from more differentiated breast cells—that dedifferentiate to a stem-cell state. “Current models of stem cell biology assume that normal and neoplastic stem cells reside at the apices of hierarchies and differentiate into non-stem progeny in a unidirectional manner,” his group wrote in 2011. “Here we identify a subpopulation of basal-like human mammary epithelial cells that departs from that assumption, spontaneously dedifferentiating into stem-like cells. Moreover, oncogenic transformation enhances the spontaneous conversion, so that non-stem cancer cells give rise to cancer stem cell (CSC)-like cells in vitro and in vivo….Normal and CSC-like cells can arise de novo from more differentiated cell types and…hierarchical models of mammary stem cell biology should encompass bidirectional inter-conversions between stem and non-stem compartments. The observed plasticity…holds important implications for therapeutic strategies to eradicate cancer.”

The daunting theory means cancer could initiate in many cell types.

In Stem Cell Reports, Wicha, head of the University of Michigan’s Comprehensive Cancer Center, agrees breast cancers spontaneously transition between two states to grow, and metastasize. But he says both appear to be stem cell states.

Max S. Wicha, MD, founding director of the University of Michigan Comprehensive Cancer CenterWicha’s paper “demonstrates CSCs may exist in two (switching) states…which may be clinically relevant in metastasis or secondary tumor formation,” said Georgia Regents University oncologist Hasan Korkaya in an email to Bioscience Technology. Uninvolved with the paper, he once worked in Wicha’s lab. “This paper is demonstrating a contrary view to Weinberg, who suggested a spontaneous conversion of non-stem cells to stem cells.”

Wicha tells Bioscience Technology the distinction is “very important.” The idea that “non-CSC's” can revert to cancer stem cells “needs to be re-explored. We propose that what has been described as induction of a CSC state by induction of (mature cells) may actually have been a transition of epithelial-like self-renewing CSCs” to another kind of CSCs that express “CSC markers CD44+/CD24-.”

The field needs to determine whether “truly differentiated cancer cells can ‘de-differentiate’ to a CSC state,” Wicha says. Sure, in the Petri dish, researchers can turn back the clock on mature cells, converting them into induced pluripotent stem (iPS) cells, Wicha says.

“Although we know that re-programming of fully differentiated normal cells to iPS cells can occur with alteration of reprograming genes, this process is extremely inefficient,” says Wicha, who is director of the University of Michigan’s Comprehensive Cancer Center. His mathematical modeling suggests the conversion rate between two breast CSC states “is far greater than the potential rate of true de-differentiation in tumors. We are now seeking to experimentally validate this concept.”

Korkaya adds: "Utilizing in situ “lineage tracing,” recent studies have demonstrated that cancer stem cell originate from tissue specific stem cells in mouse models of skin, gut and brain cancers. These studies provide further evidence for the cancer stem cell concept, suggesting that these cells initiate and maintain tumors, mediate metastasis, and contribute to treatment resistance and relapse."

Weinberg, a founder of the Whitehead Institute for Biomedical Research, discovered the first human oncogene. He feels both theories may be true. Wicha’s report of “at least two distinct stem cell-like subpopulations in breast cancers is certainly in consonance with the increasing evidence that each epithelial cell population has its own minority population of stem cells,” Weinberg tells Bioscience Technology.

He concludes: “In the mammary gland, the different subtypes of normal epithelial cells are likely to have their own respective stem-cell subpopulations. Similarly, the neoplastic derivatives of each of these cell populations are each likely to have their own subpopulations of stem cells. The major conclusions of this paper are eminently reasonable.”