Potential Modulator of NSCLC Metastasis Identified

Stefan Bekiranov, PhD

Blocking activin-A, a protein that is secreted by non-small cell lung cancer (NSCLC) cells, may prevent cancer metastasis, according to research conducted at the University of Virginia (UVA). Scientists there discovered that activin-A is overexpressed in human NSCLC tissue samples and that, in laboratory studies, blocking this protein prevented metastasis of these lung cancer cells.¹This discovery has important implications for drug development, as well as for staging and monitoring of patients with NSCLC.

During metastasis, tumor cells travel from the site of the original tumor to other places in the body. It is at this stage that cancer is most lethal. Despite breakthrough discoveries of novel drug targets and the evolution toward personalized medicine in cancer care, management of patients with metastatic cancer remains one of the toughest challenges for today’s clinicians.

Researcher Stefan Bekiranov, PhD, of the UVA department of biochemistry and molecular genetics and the UVA Cancer Center, explained, “To be able to detect metastasis when it is happening would be extremely important; it is one of the major processes that kills cancer patients. Today, studying and diagnosing cancer metastasis are challenging; the process is very transient. We do not have good markers to learn that it has begun.”

Translational cancer researchers have focused significant resources on the identification of relevant mutations and other genetic changes, as well as signaling pathways that contribute to cancer progression. In contrast, Bekiranov believes that research focused on tumor metastasis, including how cancer cells travel to new locations and specific factors that influence this process, remains untapped. He and his colleagues at UVA have taken a key step in documenting how tumor cells work in concert with various components of their microenvironment, including growth factors, such as transforming growth factor-β (TGF-ß), which initiate metastasis. Cancer cells maintain the drive toward the metastatic state by upregulating and secreting their own growth factor, activin-A, which is a TGF-ß superfamily member. Activin-A was initially discovered in the 1980s. First observed to stimulate biosynthesis and secretion of follicle-stimulating hormone from pituitary gonadotropes, activin-A was thought to be a reproductive hormone. Today, it is clear that this protein has a multitude of functions and is relevant in a variety of disease states, including cancer. Activin-A is understood to affect cell proliferation, differentiation, and apoptosis; homeostasis; metabolism; and endocrine function; as well as immune response, wound repair, and inflammation.^2-4

Data from the laboratory studies performed by Bekiranov et al at UVA, which were published in the January 15, 2015, issue ofCancer Research, showed that activin-A and other soluble growth factors are secreted by tumor cells during a critical step in NSCLC tumorigenesis, the induction of epithelial-to-mesenchymal transition (EMT).¹

In humans, EMT and its reverse process, mesenchymal-epithelial transition (MET), are important in embryonic growth, fibrosis development, wound healing, and the evolution of cancer. Because mesenchymal cells can enter the bloodstream, induction of EMT enables cancer cell invasion and metastases. Mesenchymal cells also resist apoptotic signaling, upregulate genes to promote self-renewal, and display properties of cancer-initiating cells (CIC). A sizable body of literature implicates CICs in tumor onset, maintenance, mutation accumulation, and metastasis. After conducting multiple laboratory experiments with both nonsquamous and squamous NSCLC cell lines, UVA scientists concluded that activin-A is critical to the maintenance of mesenchymal properties of CICs and promotes metastasis in NSCLC.

A cancer cell’s ability to maintain mesenchymal properties may also be relevant in early-stage cancers. Bekiranov explained, “What is sometimes underappreciated is the importance of EMT as a mechanism of resistance in the primary tumor environment. We believe EMT is critical in both local tumor growth and the metastatic setting. Primary cancer cells resist drug therapy not just through driver mutations or adaptive signaling. A potentially major mechanism by which primary tumors develop resistance is the transition to the mesenchymal state.”

Pharmaceutical researchers may be able to exploit the growing body of knowledge regarding activin-A to develop inhibitors of metastatic spread. Bekiranov believes that activin-A represents a target that can be affected by drugs.

“Developing a more specific analog of today’s activin-A inhibitors will be the first step. Such a drug has immense potential, which was one of the major points of our study. Our mechanistic experiments showed that activin-A is required for NSCLC cells to maintain their mesenchymal state. All the way through the process of cell transition, cells depend on activin-A. Drugs that block activin-A could be important in treating metastatic NSCLC, as well as cells that have undergone EMT in the primary tumor,” Bekiranov said.

Clinical Pearls

• Cancer is most lethal after it has metastasized. Identifying and targeting biologic determinants of cancer cell spread may prevent the process and enhance patient outcomes.
• Cancer scientists at UVA have observed that activin-A is critical to the maintenance of mesenchymal properties of NSCLC cells, and regulates the metastasis of these cells in laboratory studies.
• After blocking activin-A expression in laboratory models, NSCLC cells grew and formed a primary tumor, but did not metastasize.
• These discoveries may influence the development of cancer-specific activin-A inhibitors, as well as blood-based biomarkers for patients with NSCLC and other solid tumors.

In addition to prompting drug development, the UVA discoveries also suggest that activin-A might have value as a biomarker. Using a simple blood test, clinicians who are monitoring patients with localized NSCLC may be able to identify that the metastatic process has begun, before obtaining imaging evidence or the emergence of symptoms.

For patients with early-stage disease, high levels of activin-A might also assist clinicians in therapy selection.

“When cancer cells transition to the mesenchymal state, unfortunately, they tend to resist today’s therapeutics that target proliferative pathways, such as the MAP kinase pathway. If you learn that activin-A levels are high for a patient, you might approach the treatment differently. You would want to use one drug that targets primary tumor cells in the epithelial state, and another that targets cells in the mesenchymal state,” Bekiranov explained.

References

1. Wamsley JJ, Kumar M, Allison DF, et al. Activin upregulation by NF-κB is required to maintain mesenchymal features of cancer stem-like cells in non-small cell lung cancer.Cancer Res. 2015;75:426-435.
2. Chen YG, Wang Q, Lin SL, et al. Activin signaling and its role in regulation of cell proliferation, apoptosis, and carcinogenesis.Exp Biol Med. 2006;231(5):534-544.
3. Sulyok S, Wankell M, Alzheimer C, Werner S. Activin: an important regulator of wound repair, fibrosis, and neuroprotection.Mol Cell Endocrinol. 2004;225(1-2):127-132.
4. Robson NC, Wei H, McAlpine T, Kirkpatrick N, Cebon J, Maraskovsky E. Activin-A attenuates several human natural killer cell functions.Blood. 2009;113(14):3218-3225.

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