In a major breakthrough, scientists led by Elena Deryugina at The Scripps Research Institute (TSRI) identified a specific protein, Latent TGFβ Binding Protein 3—LTBP3 for short—that kicks off a cellular chain reaction resulting in early-development tumors growing new blood vessels. These vessels then act like highways to spread cancer cells throughout the body, seeding metastatic tumors very early on.
The crux discovery has to do with the “T” in LTBP3, TGFβ, a protein that has long caught the attention of cancer researchers as a target for chemotherapy drugs. Having multiple roles in healthy people and in disease, TGFβ can be both a promoter and suppressor of tumor cell growth. However, current technologies have yet to be so specific as to successfully target TGFβ’s harmful effects while leaving its normal, and vital, role in the body unhindered. Deryugina surmises that LTBP3 is the smoking gun, setting TGFβ up as a cancer-promoting factor.
“Specifically, LTBP3 appears to help tumors grow new blood vessels in a process called angiogenesis, which is critical for tumor cell intravasation, that is, when cancer cells enter into blood vessels of defined size and permeability,” notes Deryugina, Ph.D., an assistant professor at TSRI and first author of the new study. “Lower LTBP3 levels appear to be associated with better prognosis in patients with certain types of cancer.”
TSRI researchers used chick embryo tumor models and a rodent model of head and neck cancer to discover how LTBP3 is involved in the spread of aggressive tumor cells. They knocked down LTBP3 expression and secretion in human tumor cell lines representing carcinoma, head and neck carcinoma and a fibrosarcoma. In each model, the team found that without LTBP3, primary tumor cells could not metastasize efficiently.
The idea that metastasis is solely a late-stage phenomena in cancer is untrue. Standing research shows that the initial steps of tumor metastasis can occur when a primary tumor is barely detectable. It was this that sparked Deryugina’s interest in the role of LTBP3. She and her team knew that LTBP3 partners with TGFβ to regulate its secretion, activation and maturation, but wondered what else LTBP3 might control.
“Our experimental findings showed that LTBP3 is active in the very early steps of metastatic spread,” says Deryugina’s collegue and study senior author James P. Quigley, Ph.D.
Importantly, the new data is in line with other clinical findings showing LTBP3 levels can indicate better overall survival in cancer patients with early-stage head and neck carcinomas. Taken together, these findings suggest LTBP3 may be a good “upstream” drug target to treat early stage tumors without affecting more complex roles of TGFβ in other parts of the body. Researchers next plan to investigate precisely how LTBP3 and TGFβ biochemically partner in the induction of new blood vessels deep within a tumor.
Renowned metastatic cancer researcher, Danny R. Welch, Ph.D., a Fellow of the National Foundation for Cancer Research (NFCR), first discovered the pro-invasive/pro-metastasis effect of TGFβ in experiments with mammary adenocarcinoma cells in 1990. Since 1996, NFCR support for Dr. Danny Welch has enabled him to discover eight of the more than 30 functionally defined metastasis suppressor genes.
Dr. Welch’s current research includes two of these metastasis suppressors, KISS1 and BRMS1. He and his team aim to develop small molecules that mimic these domains and either suppress metastasis or maintain metastatic tumors in a dormant state. This research may target the metastasis of skin, breast, colorectal, lung, ovarian and prostate cancer.
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- Deryugina, Elena; et al. LTBP3 promotes early metastatic events during cancer cell dissemination. (January. 2018) Oncogene. DOI: 10.1038/s41388-017-0075-1