Schwann cells: a new player in the tumor microenvironment

Bunimovich, Yuri L.; Keskinov, Anton A.; Shurin, Michael R.

doi:10.1007/s00262-016-1929-z

Cited by 42 publications

(38 citation statements)

References 125 publications

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“…b-adrenergic blockade is being tested as a treatment option for several malignancies (39). In comparison, little attention has been directed at the peripheral neuroglia as a potential modulator of cancer (11). Myelinating and nonmyelinating SCs comprise the majority of the peripheral glia and are present in almost every anatomic site in the body.…”

Section: Discussionmentioning

confidence: 99%

“…While the number of investigations into the neuronal regulation of cancer has increased in recent years, the involvement of the peripheral neuroglia in cancer progression remains poorly understood (11,12). Schwann cells (SC) comprise the majority of the neuroglia of the PNS and are intimately associated with the nerve fibers, providing trophic support and a signaling scaffold for the axon (13,14).…”

Section: Introductionmentioning

confidence: 99%

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Melanoma-Induced Reprogramming of Schwann Cell Signaling Aids Tumor Growth

et al. 2019

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The tumor microenvironment has been compared with a nonhealing wound involving a complex interaction between multiple cell types. Schwann cells, the key regulators of peripheral nerve repair, have recently been shown to directly affect nonneural wound healing. Their role in cancer progression, however, has been largely limited to neuropathic pain and perineural invasion. In this study, we showed that melanoma activated otherwise dormant functions of Schwann cells aimed at nerve regeneration and wound healing. Such reprogramming of Schwann cells into repair-like cells occurred during the destruction and displacement of neurons as the tumor expanded and via direct signaling from melanoma cells to Schwann cells, resulting in activation of the nerve injury response. Melanoma-activated Schwann cells significantly altered the microenvironment through their modulation of the immune system and the extracellular matrix in a way that promoted melanoma growth in vitro and in vivo. Local inhibition of Schwann cell activity following cutaneous sensory nerve transection in melanoma orthotopic models significantly decreased the rate of tumor growth. Tumor-associated Schwann cells, therefore, can have a significant protumorigenic effect and may present a novel target for cancer therapy.Significance: These findings reveal a role of the nerve injury response, particularly through functions of activated Schwann cells, in promoting melanoma growth. Recently, similar activation of the peripheral glia was described in

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Melanoma-Induced Reprogramming of Schwann Cell Signaling Aids Tumor Growth

et al. 2019

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“…For instance, we reported that the purified murine DRG neurons can be activated by melanoma cells and, in turn, augment melanoma growth in vivo (17). Understanding that the in vivo microenvironment of peripheral nerves is created and maintained by the nerve ensheathing Schwann cells (SC), the principal glia of the PNS (18), we provided theoretical evidence that SC may aid tumor growth by promoting tumor-favorable conditions through their interaction with malignant cells and the facilitation of the immunosuppressive microenvironment (19). Although the main function of SC is to maintain the integrity of axons, SCs have been shown to increase the integrin-dependent tumor invasion on laminin in the pancreatic and the prostate cancer microenvironment (20).…”

Section: Introductionmentioning

confidence: 99%

Schwann Cells Augment Cell Spreading and Metastasis of Lung Cancer

et al. 2018

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Although lungs are densely innervated by the peripheral nervous system (PNS), the role of the PNS in the progression of lung cancer is unknown. In this study, we report that mouse adult Schwann cells (SC), the principal glial cells of the PNS, can regulate the motility of lung cancer cells and the formation of metastases SCs promoted epithelial-to-mesenchymal transition (EMT) and the motility of two lung cancer cell lines by increasing expression of Snail and Twist in tumor cells; blocking of Snail and Twist expression abolished SC-induced motility of tumor cells. SC-derived CXCL5 was responsible for EMT in lung cancer cells, as the inhibition of CXCL5 or its receptor CXCR2 reduced SC-induced expression of Snail and Twist and reduced motility in tumor cells. CXCL5/CXCR2 binding activated the PI3K/AKT/GSK-3β/Snail-Twist signaling pathway in lung cancer cells, and the PI3K inhibitor blocked CXCL5-dependent phosphorylation of AKT and GSK-3β, reduced expression of Snail/Twist, and limited tumor cell invasiveness. SC conditioning of tumor cells prior to their injection into mice significantly increased the formation of metastases in the regional lymph nodes. In summary, SCs can regulate the CXCL5/CXCR2/PI3K/AKT/GSK-3β/Snail-Twist pathway to promote EMT, invasiveness, and metastatic potential of lung cancer cells. Our results reveal a new role of the PNS in the functional organization of the tumor microenvironment and tumor progression. This study increases our understanding of how nerves and, in particular, specific glial cells, Schwann cells, in the peripheral nervous system, may help promote tumor growth and metastasis. .

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“…Neuronal fibers could interact with immune cells in the microenvironment and in a multitude of cases these interactions could be immunosuppressive and anti‐inflammatory . Recently, Keskinov et al .…”

Section: Discussionmentioning

confidence: 99%

“…Neuronal fibers could interact with immune cells in the microenvironment and in a multitude of cases these interactions could be immunosuppressive and anti-inflammatory. 38,39 Recently, Keskinov et al found that sensory neurons induced the formation of immunosuppressive microenvironment via attraction of MDSCs in melanoma. 40 FoxP3 + T cell is another type of immune regulatory cell that functions like MDSCs in prostate cancer.…”

Section: Discussionmentioning

confidence: 99%

Expression of PD‐L1 in tumor‐associated nerves correlates with reduced CD8⁺ tumor‐associated lymphocytes and poor prognosis in prostate cancer

Han

Liang

et al. 2019

Intl Journal of Cancer

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To investigate immune profile consisting of stromal PD‐L1 expression, inhibitory or non‐T‐cell inflamed tumor microenvironment that may predict response to anti‐PD‐L1/PD‐1 immunotherapy in prostate cancer, we validated the specificity of a PD‐L1 monoclonal antibody (E1L3N) and identified PD‐L1 specific expression in prostatic stromal nerve cells. PD‐L1 expression was analyzed in 73 primary prostate cancers and 7 castration‐resistant prostate cancers (CRPC) by immunohistochemistry (IHC) and resulting data from primary prostate cancers were correlated with tumor‐associated lymphocytes (TALs), clinicopathological characteristics and clinical outcome. PD‐L1 was expressed in the tumor cells in only one primary prostate cancer case and none of the CRPC. However, PD‐L1 was frequently observed in the nerve branches in the tumor‐associated stroma (69 of 73 cases, 94.5%), supported by colocalization with axonal marker PGP9.5. FoxP3‐, CD3‐ and CD8‐positive T lymphocytes were observed in 74.6% (47/63), 98.4% (62/63) and 100% (61/61) of the cases, respectively. The density of PD‐L1+ tumor‐associated nerves (TANs) was inversely correlated with that of CD8+ TALs. Higher density of PD‐L1+ TANs was significantly associated with biochemical recurrence (BCR) in Kaplan–Meier survival analysis (p = 0.016). In both univariate and multivariate Cox analysis, the density of PD‐L1+ TANs was independently prognostic of BCR. In conclusion, PD‐L1 expression is rare in prostate tumor cells but prevalent in TANs and negatively correlated with CD8+ TALs. Neuro‐immunological interaction may be a contribution to immune‐suppressive microenvironment. Combinatorial treatment regimen designs to neural PD‐L1 and TALs should be warranted in future clinical application of anti‐PD‐L1/PD‐1 immunotherapy in prostate cancer.

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Schwann cells: a new player in the tumor microenvironment

Cited by 42 publications

References 125 publications

Melanoma-Induced Reprogramming of Schwann Cell Signaling Aids Tumor Growth

Melanoma-Induced Reprogramming of Schwann Cell Signaling Aids Tumor Growth

Schwann Cells Augment Cell Spreading and Metastasis of Lung Cancer

Expression of PD‐L1 in tumor‐associated nerves correlates with reduced CD8⁺ tumor‐associated lymphocytes and poor prognosis in prostate cancer

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Schwann cells: a new player in the tumor microenvironment

Cited by 42 publications

References 125 publications

Melanoma-Induced Reprogramming of Schwann Cell Signaling Aids Tumor Growth

Melanoma-Induced Reprogramming of Schwann Cell Signaling Aids Tumor Growth

Schwann Cells Augment Cell Spreading and Metastasis of Lung Cancer

Expression of PD‐L1 in tumor‐associated nerves correlates with reduced CD8+ tumor‐associated lymphocytes and poor prognosis in prostate cancer

Contact Info

Product

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Expression of PD‐L1 in tumor‐associated nerves correlates with reduced CD8⁺ tumor‐associated lymphocytes and poor prognosis in prostate cancer