TGF-beta pathway protects against uterine cancer

January 14, 2019

Two new mouse models of uterine cancer shed light on how this disease - the most common gynecological cancer in the U.S. - happens. Led by researchers at Baylor College of Medicine, the team of scientists found that the Transforming Growth Factor beta (TGF-beta) signaling pathway in uterine cells protects against the disease by suppressing the overgrowth and transformation into cancer cells of the endometrium, the membrane lining the inside of the uterus.

The findings, which are published in two papers in the Proceedings of the National Academy of Sciences (PNAS) today, suggest potential new therapeutic strategies that could be beneficial to patients in the future.

"The TGF-beta signaling pathway regulates the development of many types of cancer, but it was not clear whether it also played a role in uterine cancer development," said corresponding author Dr. Martin M. Matzuk, director of the Center for Drug Discovery, Stuart A. Wallace Chair, Robert L. Moody, Sr. Chair and professor of pathology & immunology at Baylor College of Medicine.

To explore the role the TGF-beta pathway plays in uterine cancer, the Matzuk lab developed two new mouse models of the disease. Each mouse model tested the effect of lacking specific proteins participating in the TGF-beta pathway; one model was studied in the absence of the protein TGF-beta receptor ALK5 and the other model tested the inactivation of both Smad2 and Smad3, proteins downstream of the receptor.

"The mice lacking ALK5 developed metastatic endometrial tumors with cervical and vaginal masses. The tumors were estrogen-dependent, meaning they required estrogen to grow. When the ovaries - the natural source of estrogen - were removed, both the tumors and metastases to the lungs regressed," Monsivais said. "These and other results indicate that it is important to maintain TGF-beta signaling via ALK5 to sustain the health and normal function of the uterus." This study is in this PNAS article.

The second mouse model was developed by Dr. Maya Kriseman, reproductive endocrinology and infertility fellow in the Department of Obstetrics and Gynecology at Baylor College of Medicine, and her colleagues. In this case, the researchers genetically modified mice to lack two other proteins, Smad2 and Smad3, which transmit the signal from the TGF-beta receptors to the nucleus. Then, they assessed the effect of lacking these proteins in tumor development.

"I found that disrupting these particular proteins, Smad2 and Smad3 in mice, caused a very aggressive hyperplasia or overgrowth of the endometrium that rapidly developed into cancer and death," Kriseman said. "These effects were dependent on estrogen, which also is a characteristic of the most common type of uterine cancer in humans. These and other findings give us a better idea as to why these mice develop aggressive uterine tumors and escape normal endometrial regulation." This study can be found in this PNAS paper.

"Taken together, the findings of Monsivais and Kriseman strongly suggest that the TGF-beta pathway is a tumor-suppressor mechanism in the uterus," said Matzuk, who also is a member of the Dan L Duncan Comprehensive Cancer Center at Baylor College of Medicine. "We anticipate that the new mouse models we have generated can be further used to uncover other processes that can lead to uterine cancer."

"Dissecting the complex cascade of biological events that are necessary for protecting the uterus from cancer and for sustaining normal fertility is critical. By revealing that the TGF-beta pathway plays a protective role against uterine cancer, this work has significantly advanced our understanding of the disease and opened novel avenues for future therapeutic strategies," said Dr. William E. Gibbons, professor of obstetrics and gynecology and director of reproductive endocrinology and infertility at Baylor College of Medicine.
Financial support to Baylor College of Medicine for the two studies was provided by Eunice Kennedy Shriver National Institute of Child Health and Human Development grants R01-HD032067, R01-HD033438, and K99-HD096057 and the Institutional Research and Academic Career Development Award (IRACDA) K12-GM084897. Dr. Monsivais holds a Postdoctoral Enrichment Program Award from the Burroughs Wellcome Fund.

Other contributors to the work of Monsivais and Peng include Dr. Yibin Kang, affiliated with Princeton University and supported by the New Jersey Commission on Cancer Research Fellowship, the Brewster Foundation and National Institutes of Health grant R01-CA212410. Additional authors to the work of Kriseman and colleagues include Monsivais, Julio Agno, Ramya Masand and Chad Creighton, all at Baylor College of Medicine.

Baylor College of Medicine

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to