Impact of semaphorin expression on prognostic characteristics in breast cancer

Butti, Ramesh; Kumar, Totakura V. S.; Nimma, Ramakrishna; Kundu, Gopal C.

doi:10.2147/bctt.s135753

Cited by 17 publications

(14 citation statements)

References 76 publications

(109 reference statements)

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“…We previously provided thorough investigation of SEMA3 genes in the TCGA breast cancer patient cohort due to the fact that most of SEMA3 members have been studied or at least partially studied in breast cancer, mainly based on cell line and animal model studies [ 11 , 12 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 ]. Here we investigated how neuroplilins and plexins work coordinately with SEMA3s to promote or inhibit tumorigenesis in breast cancer tumors.…”

Section: Resultsmentioning

confidence: 99%

Characterization of Class-3 Semaphorin Receptors, Neuropilins and Plexins, as Therapeutic Targets in a Pan-Cancer Study

Zhang

Shao

2020

Cancers

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Class-3 semaphorins (SEMA3s), initially characterized as axon guidance cues, have been recognized as key regulators for immune responses, angiogenesis, tumorigenesis and drug responses. The functions of SEMA3s are attributed to the activation of downstream signaling cascades mainly mediated by cell surface receptors neuropilins (NRPs) and plexins (PLXNs), yet their roles in human cancers are not completely understood. Here, we provided a detailed pan-cancer analysis of NRPs and PLXNs in their expression, and association with key signal transducers, patient survival, tumor microenvironment (TME), and drug responses. The expression of NRPs and PLXNs were dysregulated in many cancer types, and the majority of them were further dysregulated in metastatic tumors, indicating a role in metastatic progression. Importantly, the expression of these genes was frequently associated with key transducers, patient survival, TME, and drug responses; however, the direction of the association varied for the particular gene queried and the specific cancer type/subtype tested. Specifically, NRP1, NRP2, PLXNA1, PLXNA3, PLXNB3, PLXNC1, and PLXND1 were primarily associated with aggressive phenotypes, whereas the rest were more associated with favorable prognosis. These data highlighted the need to study each as a separate entity in a cancer type- and subtype-dependent manner.

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Section: Resultsmentioning

confidence: 99%

Characterization of Class-3 Semaphorin Receptors, Neuropilins and Plexins, as Therapeutic Targets in a Pan-Cancer Study

Zhang

Shao

2020

Cancers

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“…To our knowledge, with the exception of SEMA3G, all SEMA3 family members have been at least partially studied in breast cancer. Most members showed tumour inhibiting roles while only SEMA3E was found to promote tumour invasion and metastasis [13,15,20,[35][36][37][38][39][40][41][42][43][44]. However, as mentioned above, most of the studies were conducted in cell lines or animal models.…”

Section: Sema3 Gene Family In Breast Cancermentioning

confidence: 99%

A pan-cancer study of class-3 semaphorins as therapeutic targets in cancer

Zhang

Klamer

et al. 2020

BMC Med Genomics

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Background: Initially characterized as axon guidance factors, semaphorins also have been implicated to have critical roles in multiple physiological and developmental functions, including the regulation of immune responses, angiogenesis, organ formation, and the etiology of multiple forms of cancer. Moreover, their contribution in immunity and the regulation of tumour microenvironment is becoming increasingly recognized. Here, we provide a comprehensive analysis of class-3 semaphorins, the only secreted family of genes among veterbrate semaphorins, in terms of their expression profiles and their association with patient survival. We also relate their role with immune subtypes, tumour microenvironment, and drug sensitivity using a pan-cancer study. Results: Expression profiles of class-3 semaphorins (SEMA3s) and their association with patient survival and tumour microenvironment were studied in 31 cancer types using the TCGA pan-cancer data. The expression of SEMA3 family varies in different cancer types with striking inter-and intra-cancer heterogeneity. In general, our results show that SEMA3A, SEMA3C, and SEMA3F are primarily upregulated in cancer cells, while the rest of SEMA3s are mainly down-regulated in the tested tumours. The expression of SEMA3 family members was frequently associated with patient overall survival. However, the direction of the association varied with regards to the particular SEMA3 isoform queried and the specific cancer type tested. More specifically, SEMA3A and SEMA3E primarily associate with a poor prognosis of survival, while SEMA3G typically associates with survival advantage. The rest of SEMA3s show either survival advantage or disadvantage dependent on cancer type. In addition, all SEMA3 genes show significant association with immune infiltrate subtypes, and they also correlate with level of stromal cell infiltration and tumour cell stemness with various degrees. Finally, our study revealed that SEMA3 genes, especially SEMA3C and SEMA3F may contribute to drug induced cancer cell resistance. Conclusions: Our systematic analysis of class-3 semaphorin gene expression and their association with immune infiltrates, tumour microenvironment and cancer patient outcomes highlights the need to study each SEMA3 member as a separate entity within each specific cancer type. Also our study validated the identification of class-3 semaphorin signals as promising therapeutic targets in cancer although further laboratory validation still needed.

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“…SEMA4C has been shown to be highly expressed relative to control tissues and cell lines. Its heightened expression and signaling through its cognate receptor PLXNB2 correlates to patient outcomes in some solid cancers [30]. Our results demonstrate high level cytoplasmic/membraneous SEMA4C expression in malignant primary patient tissues which suggests SEMA4C is targetable on the cell surface.…”

Section: Discussionmentioning

confidence: 67%

SEMA4C is a novel target to limit osteosarcoma growth, progression, and metastasis

Smeester

Slipek

Pomeroy

et al. 2019

Preprint

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47Semaphorins, specifically type IV, are important regulators of axonal guidance and 48 have been increasingly implicated in poor prognoses in a number of different solid 49 cancers. In conjunction with their cognate PLXNB family receptors, type IV members have 50 been increasingly shown to mediate oncogenic functions necessary for tumor 51 development and malignant spread. In this study, we investigated the role of semaphorin 52 4C (SEMA4C) in osteosarcoma growth, progression, and metastasis. We investigated 53 the expression and localization of SEMA4C in primary osteosarcoma patient tissues and 54 its tumorigenic functions in these malignancies. We demonstrate that overexpression of 55 SEMA4C promotes properties of cellular transformation, while RNAi knockdown of 56 SEMA4C promotes adhesion and reduces cellular proliferation, colony formation, 57 migration, wound healing, tumor growth, and lung metastasis. These phenotypic changes 58 were accompanied by reductions in activated AKT signaling, G1 cell cycle delay, and 59 decreases in expression of mesenchymal marker genes SNAI1, SNAI2, and TWIST1. 60Lastly, monoclonal antibody blockade of SEMA4C in vitro mirrored that of the genetic 61 studies. Together, our results indicate a multi-dimensional oncogenic role for SEMA4C in 62 metastatic osteosarcoma and more importantly that SEMA4C has actionable clinical 63 potential. 64 65 Introduction 66Osteosarcoma is a malignant, primarily pediatric tumor, of the growing long bones 67 with peak incidence in the second decade of life [1]. Derived from mesenchymal origins 68 in the pre-osteoblastic lineage, osteosarcomas arise from the failure of osteoblasts to 69 differentiate into mature bone-building cells [2]. Osteosarcomas are commonly typified by 70 their heterogeneity, genomic instability, and frequency of systemic metastasis primarily 71 to the lungs [3, 4]. Despite advances in chemotherapy regimens and surgical resection, 72 survival rates for patients with osteosarcoma have remained stagnant for more than four 73 decades [5]. The complex nature of osteosarcoma presents unique difficulties with 74 respect to elucidating novel therapeutic targets and identifying treatment strategies that 75 may prove most effective, particularly across individual patients. Given this, it is critically 76 important to better understand not only the mechanisms specific to osteosarcoma 77 development and progression, but most importantly metastasis, in order to develop better 78 treatment options for patients with this devastating disease. 79 Semaphorins are a family of membrane-bound and soluble proteins that modulate 80 a whole host of cellular functions including differentiation, cytoskeletal rearrangement, 81 and motility [6]. Interestingly, semaphorin family members have been reported to mediate 82 many hallmarks of cancer including cellular proliferation, angiogenesis, and immune 83 escape [7-9]. Recent evidence from studies of the SEMA4-PLXNB family of axonal 84 guidance molecules in normal bone cells suggests that osteoclastic exp...

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Impact of semaphorin expression on prognostic characteristics in breast cancer

Cited by 17 publications

References 76 publications

Characterization of Class-3 Semaphorin Receptors, Neuropilins and Plexins, as Therapeutic Targets in a Pan-Cancer Study

Characterization of Class-3 Semaphorin Receptors, Neuropilins and Plexins, as Therapeutic Targets in a Pan-Cancer Study

A pan-cancer study of class-3 semaphorins as therapeutic targets in cancer

SEMA4C is a novel target to limit osteosarcoma growth, progression, and metastasis

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