Herein we describe increased VEGFA and SEMA

Herein, we describe increased VEGFA and SEMA3A expression in bone marrow mitoxantrone from de novo AML patients and the possible dominant effect of SEMA3A, suggesting that SEMA3A could control the effects caused by VEGFA. However, some questions remain: Why is SEMA3A expression increased in BMSCs from MDS and secondary AML patients? If SEMA3A inhibits the effects caused by VEGFA, why do patients still exhibit uncontrolled proliferation of leukemic blasts? Little is known regarding the effect of SEMA3A in bone marrow microenvironment. Due to their tissue-specific effect, SEMA3A could delay effects caused by other growth factors or could act upon the pathogenesis of myeloid diseases. Considering only VEGFA and SEMA3A interaction in de novo AML patient bone marrow, our data suggest that SEMA3A may have a therapeutic role through inhibition of the effects caused by VEGFA. Under physiological conditions, VEGF165 and SEMA3A have been suggested to be involved in a negative feedback. In endothelial cells, increased VEGF165 expression induces increased SEMA3A expression as a part of an angiogenic balance; and this feedback is dysregulated in malignant processes (Vacca et al., 2006; Catalano et al., 2004). Despite these results, we are aware that SEMA3A protein alone is not capable of reversing the clinical condition of patients, as many factors contribute to AML pathogenesis, acting in synergy with VEGFA (Kornblau et al., 2010). VEGFA has been a target of cancer treatment, including AML and many inhibitors of pathways triggered by VEGFA have been produced and are under test in clinical protocols (Garcia-Manero et al., 2015; Gupta et al., 2013). The use of SEMA3A may add new possibilities to improve this treatment. However, although our study provides insights regarding the clinical relevance of SEMA3A and VEGFA in MDS and AML, taking into consideration the heterogeneity of these diseases, any application as a possible treatment would no doubt require additional studies in large and unselected AML patient cohorts, necessary to clarify whether there are exceptional subsets of patients where this effect is weaker or cannot be seen.
Conclusion Our results suggest that VEGFA overexpression confers advantages to leukemic cells, by increasing their proliferation, and SEMA3A protein may partially reverse the effects caused by VEGFA. Thus, the combined administration of VEGFA inhibitors and SEMA3A protein may be beneficial for treatment of AML patients. The following are the supplementary data related to this article.
Conflict of interest
Acknowledgements The authors would like to thank Dra. Maria Heloisa de Souza Lima Blotta and her student Livia Furquim de Castro for the assistance in the nucleofection assays. Raquel S Foglio for English revision and Tereza Salles for her valuable technical assistance. This work was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP).
Introduction With an estimate of >13.7 million cancer survivors in the United States (Siegel et al., 2012) there is concern regarding long-term effects of chemotherapy. Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most common and potentially permanent side effects of modern chemotherapy that can result in dose reduction or cessation of therapy (Brewer et al., 2016). CIPN may develop in 20–40% of cancer patients as a consequence of treatment with platinum analogues (cisplatin, oxaliplatin, carboplatin), taxanes (paclitaxel, nab-paclitaxel, docetaxel), vinca alkaloids (vincristine), proteasome inhibitors (bortezomib), epothilones or other chemotherapeutics (Chu et al., 2015; Grisold et al., 2012). Differences in structural and mechanistic properties among various chemotherapeutic agents contribute to variations in clinical presentation including numbness, loss of proprioceptive sense, tingling, pins and needles sensations, hyperalgesia or allodynia in the hands or feet in a stocking-glove distribution (Brewer et al., 2016).