Stem Cell Program | Cancer

When found early many types of cancer are treatable through chemotherapy or radiation. However, there are certain cancers that keep on growing. One possible explanation for this phenomenon is that cancer cells with stem-cell-like properties enable cancers to perpetuate even after treatment. These particular cells are known as cancer stem cells.

While doctors at Boston Children’s Hospital continue to use innovations to treat cancer, stem cell researchers have taken an interest in what cancer stem cells can teach us about how to tackle the disease.

Our work with stem cells and cancer includes:

• optimizing treatment of leukemia and other blood cancers with bone marrow transplants
• phase I trial for a drug to boost blood cell production in leukemia patients undergoing treatment
• distinguishing leukemia stem cells from healthy blood stem cells
• searching for cancer stem cells in lung cancer
• finding new ways to attack skin cancer stem cells

Leukemia

Leukemia is a cancer in which the bone marrow overpopulates the blood with immature white blood cells. The bone marrow transplant treatment is the first example of stem-cell-based therapy. Hematopoietic (blood-forming) stem cells from a donor are used to replace a patient’s diseased marrow. At Boston Children’s, we use hematopoietic stem cell transplants to treat leukemia.

Grant Rowe, MD PhD, an affiliate member of the Stem Cell Program, is interested in the differences between normal and leukemic blood stem cells and understanding how leukemia stem cells can be targeted. He is also interested in how blood stem cells vary across ages — studies with implications for improving bone marrow transplantation.

Leonard Zon, MD discovered a new use for the drug PGE2, that may boost production of blood stem cells in patients undergoing stem cell transplantation for leukemia or lymphoma. This new use of PGE2 started Phase I clinical trials in May 2009.

George Daley, MD, PhD, and Thorsten Schlaeger, PhD, are interested in engineering platelets from pluripotent stem cells. An off-the-shelf, renewable source of platelets would decrease reliance on healthy donor platelets for patients undergoing bone marrow transplantation or receiving chemotherapy.

Lung cancer

Lung cancer is a leading cause of death from cancer in the U.S. and worldwide. This is because most patients are not diagnosed until they have advanced lung cancers and are faced with few or no therapeutic options.

Carla Kim, PhD, a Boston Children’s stem cell researcher, was the first person to discover a group of stem cells from the adult mouse lung called bronchioalveolar stem cells (BASCs). Kim discovered how to extract these cells from lung tissue to study their growth. She also showed that mutated BASCs are the source of certain lung cancers, such as adenocarcinoma. In humans, adenocarcinoma is an aggressive form of lung cancer that, in later stages, is often resistant to treatment. The discovery of BASCs has provided a new way for scientists to better understand the way stem cells function and how they are controlled in a normal lung or altered in lung diseases.

Recent work in other solid tumors indicates that only some of the cells within a tumor are required for tumor growth. These cancer cells have been named cancer stem cells. Cancer stem cells may be part of the cause of lung cancer cell resistance to therapy, but it is not yet known if lung cancers contain cancer stem cells. Kim’s lab has developed a way to determine if lung tumors have cancer stem cells. They can create lung tumors in mice or use lung cancer patient samples, isolate special subgroups of tumor cells, and re-grow the lung tumors in recipient mice. Observing which cell groups can grow tumors will zero in on what helps to sustain lung cancer. The lab has already found a cancer stem cell population in mouse lung tumors, and is now searching for similar cells in human lung cancer tissue samples.

Richard Gregory, PhD, recently identified a role for the RNA modification enzyme METTL3 in regulation of translation of oncogenic mRNAs and is required for progression of lung cancer.

Melanoma

Melanoma is a common cause of cancer mortality in the U.S., with many patients diagnosed at advanced stages. Leonard Zon, MD, has developed zebrafish-based models of melanoma where he recently identified a novel tumor suppressor, SPRED1, that is often mutated in human mucosal melanoma. This followed a previous study where he showed that the primitive neural crest identity can be activated during melanoma formation.

Gastrointestinal cancer

Fernando Camargo, PhD studies the role of the Hippo-YAP pathway in liver health and liver cancer. His laboratory recently uncovered NUAK2 as a novel target of the activated YAP pathway that often occurs in liver cancer, and that targeting of NUAK2 might provide a new therapeutic modality. More recently, Camargo’s group demonstrated that YAP activity acted to suppress tumor growth in the intestine.

Outsmarting cancer

The standard protocol for cancer chemotherapy is to give the maximum tolerated dose — a regimen that's brutal to experience, yet doesn't always kill the cancer. Many scientists are convinced that tumors are formed and fed by a small but critical group of cells known as cancer stem cells. These cells, they believe, can endlessly replace themselves and form other tumor cell types, just as normal stem cells form different tissues in a developing embryo. They could represent the most appropriate target in cancer therapy.

Scott Armstrong, MD, PhD, a pediatric oncologist at Dana-Farber/Boston Children's Cancer and Blood Disorders Center and affiliate member of the Stem Cell Program at Boston Children’s, likens cancer stem cells to queen bees: A hive collapses only if the queen is destroyed; if she isn’t, the colony re-forms. White makes another analogy.

Research has accelerated dramatically since the first cancer stem cells were identified in a human leukemia in the 1990s. But exactly what a cancer stem cell is or isn’t has yet to be defined.

Ultimately, the most important question is how these cells help tumors thrive and spread, and how to eliminate or neutralize them. Kim, White, and Armstrong are exploring these questions, looking at three different cancers.

Clarifying melanoma

In a room filled with tanks full of tiny zebrafish — some striped, others yellowish, still others genetically engineered as albinos — White points out his latest creation, dubbed Casper. This ghost-like breed, with its clearly visible internal organs, is helping with the study metastatic disease, an often fatal spread of cancer to another part of the body.

White’s studies, conducted in the laboratory of Leonard Zon, MD, Director of the Stem Cell Program at Boston Children’s , focus on metastatic melanoma. Because Casper’s skin is transparent, White can directly observe melanoma’s spread by viewing the fish under a microscope. Some tumor cells quickly break off to go elsewhere in its body. The mobility of these tumor cells, at least in melanoma, may be integral to metastasis, he believes.

Taking another approach, Markus Frank, MD, an affiliate member of the Stem Cell Program at Boston Children’s, in the Transplantation Research Center of Boston Children’s and Brigham and Women’s Hospital, works with mice bearing human melanomas. In 2008, he showed that melanoma stem cells carry a protein on their surface, ABCB5, that makes them chemotherapy-resistant. But they also showed that melanoma stem cells can be targeted for destruction — and tumors inhibited — by using antibodies against that very protein. In early 2010, Frank and colleagues further demonstrated that melanoma stem cells help the cancer evade our immune defenses by actually lulling the immune system into shielding the cancer from immune attack. In revealing this clever dodge, the study also suggests several possible ways of countering it.

New light on lung cancer

Although lung cancer is the number one cause of cancer death worldwide, it remains one of the most poorly funded cancers in terms of research, largely because of the stigma associated with smoking. Kim, who started her lab at Boston Children’s in 2006, is one of the few people in the world who’s carved out a niche in lung stem cell research, studying both cancer and normal lung cells.

During her postdoctoral fellowship, Kim was the first to isolate bronchioalveolar stem cells (BASCs), a type of lung stem cell, from adult mice. She also found that the most common genetic mutation in lung cancer appears to transform BASCs into the bad guys of adenocarcinoma, an aggressive form of lung cancer.

By transplanting lung tumor cells from one mouse to another, Kim has observed that in certain cases, only the BASC-like cells from tumors can grow when implanted in laboratory animals. These cells, she says, may be the stem cells in lung cancer. She’s now examining the activity of their genes to see what makes them different from normal lung stem cells.

Kim is also searching mouse lungs for other cells with “stem” properties, observing which cell types are involved in repairing lung injuries. She hopes to learn whether normal lung stem cells could be used as a therapy for cystic fibrosis, the defective lungs of premature infants and other pulmonary problems.

Targeting leukemia stem cells

Today the most common leukemias have cure rates of approximately 80 percent. But children with certain rare forms of the disease may initially go into remission, only to suffer a fatal relapse. Mixed lineage leukemia (MLL) is one example, sharing features of two major childhood blood cancers, acute lymphoblastic leukemia (ALL) and acute myelogenous leukemia (AML). Armstrong, who studies MLL, believes that cancer stem cells could be initiating relapse and is keen to find new and better therapies.

Armstrong  showed that in MLL, certain progenitor cells that give rise to white blood cells inappropriately acquire stem-like, self-renewing qualities through a rearrangement of their chromosomes. This causes the halves of two different blood proteins to fuse. When this hybrid protein was injected into progenitor cells from mice, it activated genes that made the cells turn cancerous and stem-cell-like. 

Scientists don’t necessarily agree that all or even most tumors are driven by stem cells, and while it seems fairly clear that stem-like cells can initiate relapse, the origins, characteristics and role of such cells probably vary from cancer to cancer. What scientists are learning is that cancer stem cells are as diverse as cancer itself.

Ultimately, researchers envision two sets of cancer treatments—classic chemotherapy, which shrinks most of a tumor, and new therapies aimed at cancer stem cells. Understanding what makes stem cells tick, and what might make them prone to turn cancerous, is crucial.

Two fundamental processes in biology — stem cell generation and carcinogenesis—are in fact closely related. The laboratories of George Q. Daley, MD, PhD and Richard Gregory, PhD, are exploring this relationship at the molecular level, showing how a factor called Lin-28, which is associated with breast and lung cancer, makes a cell more prone to de-differentiate — revert to a less mature, unspecialized, stem-like state. Daley recently showed that Lin-28 is associated with the pathogenesis and poor prognosis of neuroblastoma, a pediatric cancer caused by abnormal proliferation of immature nerve cells. Such findings provide a better understanding of Lin-28's role in carcinogenesis and open new avenues in the development of novel therapies. Gregory is seeking drugs that mimic the effect of Lin-28 to help generate pluripotent stem cells, as well as drugs that block Lin-28 to inhibit cancers. Read more. 

It may seem paradoxical that stem cells can be so dangerous — driving a cancer — yet are also sought after for cures. Because stem cells are capable of giving rise to different types of cells, they can be used to produce anti-tumor immune cells that act as living drugs. Daley is seeking to use health stem cells as an inexhaustible cell source to generate off-the-shelf T-cells for CAR T-cell therapy. This therapy, which engineers T-cells to recognize and attack the tumor, is the vanguard of cancer immunotherapy and has shown great therapeutic efficacy against blood cancers.