Transcription Factor Promotes Progression of Ovarian Cancer

A member of the Hox family of transcription factors, HOXB13, may contribute to tumor progression in some ovarian cancers and might serve as a biomarker for cancer aggressiveness, according to a study in the Oct. 23 Proceedings of the National Academy of Sciences. Ovarian cancer is notoriously difficult to detect, and an estimated one in 71 women will develop the disease in her lifetime, according to the National Cancer Institute.

Courtesy Sandra Orsulic

Tumor acceleration. In the company of activated K-ras, HOXB13 enhances tumor growth in mouse ovarian cancer cells that were injected subcutaneously (right). Without HOXB13, the control mouse ovarian cancer cells that were infected with green fluorescent protein (GFP) grew at a slower rate.

The lab of Dennis Sgroi, HMS associate professor of pathology at Massachusetts General Hospital, usually investigates the role of HOXB13 in breast cancer. Many breast tumors rely on the binding of estrogen to the estrogen receptor (ER) to promote tumor growth. The antihormonal drug tamoxifen competes with estrogen for the ER, thereby impeding tumorigenesis.

In a study three years ago, Sgroi and his colleagues observed that HOXB13 was highly expressed in aggressive ER-positive breast cancers that do not respond to tamoxifen.

Since the ovary, like the breast, is hormonally regulated, Sgroi’s lab joined forces with the ovarian cancer lab of Sandra Orsulic, an HMS assistant professor of pathology at MGH, to determine whether this drug resistance or tumorigenesis was linked to the Hox protein in the ovary. “We thought, ‘Maybe HOXB13 plays a role in the ovarian neoplasia, too,’” said Sgroi. “Perhaps this gene is playing a role in resistance to tamoxifen.”

The two labs reconfirmed that HOXB13 is highly expressed in a subset of ovarian cancer cases, but has little or no expression in normal ovarian tissue. When they knocked down HOXB13 in human ovarian cancer cell lines, the researchers found reduced tumor colony formation.

Sgroi and Orsulic, co–senior authors on the paper, and their colleagues also found that human cells with an ectopic expression of HOXB13 showed other telltale signs of cancer: spindlelike morphology, loss of contact inhibition accompanied by three-dimensional and migratory growth, a reduced rate of cell apoptosis, and an enhanced rate of proliferation. Notably, ectopic expression of HOXB13 resulted in decreased sensitivity to tamoxifen-induced apoptosis.

Orsulic developed two mouse cell lines with mutations commonly seen in ovarian cancer, including alterations in p53, c-myc, K-ras, and Akt.

“The only difference in [the mouse cell] lines is that one has Akt and one has ras. When we put HOXB13 into the one that has ras, we had increased tumor growth,” said Sgroi. “In Akt, we did not see tumorigenesis. Somehow HOXB13 collaborates with ras.”

Until HOXB13’s role in relation to ER–positive ovarian cancer is delineated, both Sgroi and Orsulic suggest that the protein can be used as a biomarker, reflecting its role as a functional regulator of antihormonal resistance in human ovarian cancer.

The researchers are now investigating the way HOXB13 interacts with ras in the context of antihormonal therapy with drugs like tamoxifen.

—Laura Geggel

Immune Cells Found to Fuel Endometriosis

Dendritic cells have been caught red handed for supporting angiogenesis that may lead to endometriosis.

Almost every woman has retrograde menstruation, the suspected root of endometriosis, but usually the immune system digests tissue that has regressed through the fallopian tubes and into the peritoneal cavity.

Ofer Fainaru, HMS research fellow in the Vascular Biology Program at Children’s Hospital Boston, and his colleagues wanted to learn why endometriosis occurs in 10 to 15 percent of women and how the condition could be interrupted. “If there is a problem in immune cell function, the shed endometrial tissue is not cleared from the peritoneal cavity, and it implants, vascularizes, and grows,” Fainaru said.
Fainaru completed his research in the lab of Judah Folkman, the Julia Dyckman Andrus professor of pediatric surgery at HMS and CHB and the study’s senior author. Folkman is credited with discovering that cancer tumors are generally angiogenesis-dependent. Endometriosis implants share this dependency.

“These implants are behaving very much like tumors in the way that they induce their own vascularization,” said Fainaru, lead author of the murine study, which was published online in FASEB Journal on Sept. 14 and will appear in the February print edition.

Fainaru and his colleagues surgically induced endometriosis in mice and detected significant angiogenesis eight days later. Analysis of the lesions showed they were infiltrated with immature dendritic cells, expressing the angiogenic marker vascular endothelial growth factor receptor 2 (VEGFR-2). By expressing VEGFR-2, a receptor normally expressed on endothelial cells, which line blood vessels, the dendritic cells may shift to a proangiogenic role, which is uncommon for immune cells.

“We showed that by implanting dendritic cells into the peritoneal cavity, they were incorporated into the lesions and caused the lesions to grow and become more vascularized,” Fainaru said.

He and his colleagues compared these findings with cancer angiogenesis using a mouse melanoma tumor model and saw similar results. The injected dendritic cells caused enhanced tumor growth and increased angiogenesis when compared to controls.

Although there is some controversy about whether dendritic cells actually incorporate into tumor vessel walls, as reported in a 2004 study in Nature Medicine, or whether they are strategically placed around the vessels, the cells significantly contribute to the process of angiogenesis, Fainaru said.

The current treatment for endometriosis involves surgical removal of the implants and hormonal suppression thereafter, but the painful condition often recurs. Fainaru next plans to ablate dendritic cells locally in his murine model to learn if endometriosis is dependent on these cells. If it is, he envisions treating the immune cells locally in the peritoneal cavity, thereby blocking or otherwise disrupting the progression of angiogenesis and endometriosis itself.

—Laura Geggel

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