SEMAPHORINS and their receptors: focus on the crosstalk between melanoma and hypoxia

Abstract

Hypoxia, a condition of oxygen deprivation, is considered a hallmark of tumor microenvironment regulating several pathways and promoting cancer progression and resistance to therapy. Semaphorins, a family of about 20 secreted, transmembrane and GPI-linked glycoproteins, and their cognate receptors (plexins and neuropilins) play a pivotal role in the crosstalk between cancer and stromal cells present in the tumor microenvironment. Many studies reported that some semaphorins are involved in the development of a permissive tumor niche, guiding cell-cell communication and, consequently, the development and progression, as well as the response to therapy, of different cancer histotypes, including melanoma.In this review we will summarize the state of art of semaphorins regulation by hypoxic condition in cancer with different origin. We will also describe evidence about the ability of semaphorins to affect the expression and activity of transcription factors activated by hypoxia, such as hypoxia-inducible factor-1. Finally, we will focus our attention on findings reporting the role of semaphorins in melanocytes transformation, melanoma progression and response to therapy. Further studies are necessary to understand the mechanisms through which semaphorins induce their effect and to shed light on the possibility to use semaphorins or their cognate receptors as prognostic markers and/or therapeutic targets in melanoma or other malignancies.

Sema4D silencing increases the sensitivity of nivolumab to B16-F10 resistant melanoma via inhibiting the PI3K/AKT signaling pathway

“…Semaphorins is involved in regulating tumor growth and metastasis. Especially in the tumor microenvironment, the disturbance between different cell types can control the development and progression of cancer ( Lontos et al, 2018 ; Valentini et al, 2021 ). Semaphorin 4D (Sema4D) is a member of the semaphorins, which plays a important role in the progress of immunoregulatory, platelet inactivation, angiogenesis stimulation and bone formation regulation ( Lontos et al, 2018 ).…”

SEMA6A/RhoA/YAP axis mediates tumor-stroma interactions and prevents response to dual BRAF/MEK inhibition in BRAF-mutant melanoma

“…Semaphorins belong to a family including more than 20 members; some of them have been shown to modulate angiogenesis, invasiveness, and metastatization by regulating monomeric GTPases, cell-substrate adhesion, and cytoskeletal dynamics [ 18 – 20 ]. More recently, the involvement of semaphorins in the complex signal exchange between tumor and its microenvironment is emerged and supported by a large body of evidence [ 21 – 29 ].…”

Dongjun Jiang, Xiaoli Chen, Xiuting Li, Jian Qiu, Peng Xu, Xuezhi Li

“…In 1993, semaphorin was first identified in the developing chicken nervous system which can regulate axonal guidance [1]. Since then, semaphorins and their receptors have been recognized as important factors in neural network development, even playing a dominant role [2,3]. Subsequently, they are also identified to be involved in cardiovascular and skeletal development, as well as in the regulation of the immune system, and their deregulation has been found in neurological diseases, cardiovascular diseases, immune diseases, cancer, etc.…”