Activin A: an emerging target for improving cancer treatment?

Abstract

Introduction: Activin A is involved in the regulation of a surprisingly broad number of processes that are relevant for cancer development and treatment; it is implicated in cell autonomous functions and multiple regulatory functions in the tumor microenvironment. Areas covered: This article summarizes the current knowledge about activin A in cell growth and death, migration and metastasis, angiogenesis, stemness and drug resistance, regulation of antitumor immunity, and cancer cachexia. We explore the role of activin A as a biomarker and discuss strategies for using it as target for cancer therapy. Literature retrieved from Medline until 25 June 2020 was considered. Expert opinion: While many functions of activin A were investigated in preclinical models, there is currently limited experience from clinical trials. Activin A has growth-and migration-promoting effects, contributes to immune evasion and cachexia and is associated with shorter survival in several cancer types. Targeting activin A could offer the chance to simultaneously limit tumor growth and spreading, improve drug response, boost antitumor immune responses and improve cancer-associated or treatment-associated cachexia, bone loss, and anemia. Nevertheless, defining which patients have the highest likelihood of benefiting from these effects is challenging and will require further work.

Targeting the Activin Receptor Signaling to Counteract the Multi-Systemic Complications of Cancer and Its Treatments

“…In patients with colorectal and lung cancer, high circulating activin A levels were associated with cancer cachexia [144,[147][148][149], along with an independent negative prognostic impact [144] and reduced chemotherapy response [148], although in some other cancers, decreased activin-signaling was also observed [150]. In addition, based on a study by Miyamoto et al, a polymorphism in the activin A gene (INHBA) was found to predict survival in refractory metastatic colorectal cancer patients treated with regorafenib [151].…”

“…Although APR has been associated with impaired survival in humans [181] and in mice, whether this represents the potential additional mechanism by which sACVR2B alleviates cachexia [13,35] remains far from being elucidated. Interestingly, activin A was shown to act in a paracrine fashion to stimulate melanoma growth and metastasization [206], thus suggesting that ACVR2 ligand blockers may simultaneously help in rescuing both muscle mass and immune function, hence also preventing tumor progression and cachexia [150]. Indeed, considering that activin A exerts pro-tumorigenic functions by promoting immunosuppressive activities in macrophages and Treg cells [207], ACVR2 ligand blockade may contribute to avoid tumor immuneescape, explaining the reported impact of sACVR2B on tumor growth and metastatic spread, independently from the presence of cachexia.…”

Clinical relevance of circulating activin A and follistatin in small cell lung cancer

“…Yet, its role in tumor development and progression is contradictory and depends on the tumoral entity [13,16]. In addition to its contradictory effects on cell growth, apoptosis, migration, invasion and metastasis formation, ActA is capable to affect the tumor microenvironment as well [17][18][19][20][21]. It has been shown that ActA has growth-limiting activity in prostate-, breast-, liver-and colon cancer and also in diffuse large B-cell lymphoma.…”

“…It has been shown that ActA has growth-limiting activity in prostate-, breast-, liver-and colon cancer and also in diffuse large B-cell lymphoma. Downregulation of activin receptors or mutations in the activin signaling pathways are frequently detected in these malignancies, which decrease its antitumoral effects [17,22]. On the contrary, in esophageal carcinoma, lung adenocarcinoma (LADC), malignant pleural mesothelioma (MPM) and cancers of the skin, pancreas, ovary, and head and neck region, ActA shows increased expression levels and stimulates cell growth and proliferation [16,17,[23][24][25][26].…”

“…Downregulation of activin receptors or mutations in the activin signaling pathways are frequently detected in these malignancies, which decrease its antitumoral effects [17,22]. On the contrary, in esophageal carcinoma, lung adenocarcinoma (LADC), malignant pleural mesothelioma (MPM) and cancers of the skin, pancreas, ovary, and head and neck region, ActA shows increased expression levels and stimulates cell growth and proliferation [16,17,[23][24][25][26]. In addition, elevated ActA expression is associated with higher metastatic potential in primary non-small cell lung cancer (NSCLC) as well [27].…”