an-in-vivo-murine-sciatic-nerve-model-of-perineural-invasion

An <em>In Vivo</em> Murine Sciatic Nerve Model of Perineural Invasion

Cancer cells invade nerves through a process termed perineural invasion (PNI), in which cancer cells proliferate and migrate in the nerve ...

Mount Sinai Hospital

Leukemia cutis (LC) is the infiltration of the epidermis, dermis, or subcutis by neoplastic leukocytes, resulting in clinically identifiable cutaneous lesions. Electron-based radiation therapy (RT) is often used in the treatment of LC; however, modern studies of RT are lacking. We reviewed our experience to analyze treatment response, disease control, and toxicity associated with RT in order to develop treatment recommendations for patients with LC.

Radiation therapy for leukemia cutis.

The ability of cancer cells to invade along nerves is associated with aggressive disease and diminished patient survival rates. Perineural invasion (PNI) may be mediated by nerve secretion of glial cell line-derived neurotrophic factor (GDNF) attracting cancer cell migration through activation of cell surface Ret proto-oncogene (RET) receptors. GDNF family receptor (GFR)α1 acts as coreceptor with RET, with both required for response to GDNF. We demonstrate that GFRα1 released by nerves enhances PNI, even in the absence of cancer cell GFRα1 expression. Cancer cell migration toward GDNF, RET phosphorylation, and MAPK pathway activity are increased with exposure to soluble GFRα1 in a dose-dependent fashion. Dorsal root ganglia (DRG) release soluble GFRα1, which potentiates RET activation and cancer cell migration. In vitro DRG coculture assays of PNI show diminished PNI with DRG from GFRα1(+/-) mice compared with GFRα1(+/+) mice. An in vivo murine model of PNI demonstrates that cancer cells lacking GFRα1 maintain an ability to invade nerves and impair nerve function, whereas those lacking RET lose this ability. A tissue microarray of human pancreatic ductal adenocarcinomas demonstrates wide variance of cancer cell GFRα1 expression, suggesting an alternate source of GFRα1 in PNI. These findings collectively demonstrate that GFRα1 released by nerves enhances PNI through GDNF-RET signaling and that GFRα1 expression by cancer cells enhances but is not required for PNI. These results advance a mechanistic understanding of PNI and implicate the nerve itself as a key facilitator of this adverse cancer cell behavior. 

GFRα1 released by nerves enhances cancer cell perineural invasion through GDNF-RET signaling.

Perineural invasion is a form of cancer progression where cancer cells invade along nerves. This behavior is associated with poor clinical outcomes; therefore, it is critical to identify novel ligand-receptor interactions between nerves and cancer cells that support the process of perineural invasion. A proteomic profiler chemokine array was used to screen for nerve-derived factors secreted from tissue explants of dorsal root ganglion (DRG), and CCL2 was identified as a lead candidate. Prostate cancer cell line expression of CCR2, the receptor to CCL2, correlated closely with MAPK and Akt pathway activity and cell migration towards CCL2 and DRG. In vitro nerve and cancer coculture invasion assays of perineural invasion demonstrated that cancer cell CCR2 expression facilitates perineural invasion. Perineural invasion is significantly diminished in coculture assays when using DRG harvested from CCL2(-/-) knockout mice as compared with control CCL2(+/+) mice, indicating that CCR2 is required for perineural invasion in this murine model of perineural invasion. Furthermore, 20 of 21 (95%) patient specimens of prostate adenocarcinoma with perineural invasion exhibited CCR2 expression by immunohistochemistry, while just 3 of 13 (23%) lacking perineural invasion expressed CCR2. In summary, nerve-released CCL2 supports prostate cancer migration and perineural invasion though CCR2-mediated signaling.

The chemokine (CCL2-CCR2) signaling axis mediates perineural invasion.

Perineural invasion (PNI) is a frequent pathological finding in head and neck cancers. When adjuvant radiation to cranial nerves at risk in head and neck cancers with PNI is considered, there is a need for consensus on which nerves are at risk and how to contour these nerves. This contouring guide attempts to address this need.

A contouring guide for head and neck cancers with perineural invasion.

We are reporting a case of a 62-year-old African American woman with a history of gastric MALT lymphoma successfully treated with radiation who presented with a laryngeal MALT lymphoma 4 years after her original diagnosis. She received definitive radiation with a complete response. The case presented is unique for the rare presentation of a MALT lymphoma in the larynx, especially in light of the patient's previously treated gastric MALT lymphoma years ago. 

A Case of a Laryngeal MALT Lymphoma in a Patient with a History of Gastric MALT.

We are reporting a case of a 34-year-old woman with occult primary breast cancer discovered after initially presenting with neurological symptoms. She was successfully treated with neoadjuvant chemotherapy followed by definitive axillary lymph node dissection and ipsilateral whole breast radiotherapy. The case presented is unique due to the rarity of occult primary breast cancer, especially in light of her initial confounding neurological signs and symptoms, which highlights the importance of careful staging. 

A unique presentation of occult primary breast cancer with a review of the literature.

We observed a number of patients who developed Lhermitte's sign (LS) following radiation to the head and neck (H/N), since instituting volumetric modulated arc therapy (VMAT). We aimed to investigate the incidence of LS following VMAT-based RT without chemotherapy, and determine the dosimetric parameters that predict its development. We explored whether the role of inhomogeneous dose distribution across the spinal cord, causing a "bath-and-shower" effect, explains this finding.

Lhermitte's Sign following VMAT-Based Head and Neck Radiation-Insights into Mechanism.

We are reporting a case of a 91-year-old male with a primary malignancy of the right parotid gland with radiographic thrombus extension within the right external jugular vein. He was treated with palliative radiation therapy to the right parotid mass with a marked clinical response. The rarity of this occurrence as documented in the review of the literature provides for uncertainty with regard to proper management. Radiographic evidence of thrombus in the absence of clinical manifestations, the role of anticoagulation, and the proper radiation target delineation were all challenges encountered in the care of this patient. Our case represents a rare occurrence with unique radiologic findings that has implications for management. 

Radiographic Thrombus within the External Jugular Vein: Report of a Rare Case and Review of the Literature.

Nerves enable cancer progression, as cancers have been shown to extend along nerves through the process of perineural invasion, which carries a poor prognosis. Furthermore, the innervation of some cancers promotes growth and metastases. It remains unclear, however, how nerves mechanistically contribute to cancer progression. Here, we demonstrated that Schwann cells promote cancer invasion through direct cancer cell contact. Histological evaluation of murine and human cancer specimens with perineural invasion uncovered a subpopulation of Schwann cells that associates with cancer cells. Coculture of cancer cells with dorsal root ganglion extracts revealed that Schwann cells direct cancer cells to migrate toward nerves and promote invasion in a contact-dependent manner. Upon contact, Schwann cells induced the formation of cancer cell protrusions in their direction and intercalated between the cancer cells, leading to cancer cell dispersion. The formation of these processes was dependent on Schwann cell expression of neural cell adhesion molecule 1 (NCAM1) and ultimately promoted perineural invasion. Moreover, NCAM1-deficient mice showed decreased neural invasion and less paralysis. Such Schwann cell behavior reflects normal Schwann cell programs that are typically activated in nerve repair but are instead exploited by cancer cells to promote perineural invasion and cancer progression. 

Schwann cells induce cancer cell dispersion and invasion.

Perineural invasion (PNI) is the neoplastic invasion of nerves. PNI is widely recognized as an important adverse pathological feature of many malignancies, including pancreatic, prostate, and head and neck cancers and is associated with a poor prognosis. Despite widespread acknowledgment of the clinical significance of PNI, the mechanisms underlying its pathogenesis remain largely unknown. Recent theories of PNI pathogenesis have placed a significant emphasis on the active role of the nerve microenvironment, with PNI resulting from well-orchestrated reciprocal interactions between cancer and host. Elucidating the mechanisms involved in PNI may translate into targeted therapies for this ominous process. 

Mechanisms of Perineural Invasion.

We are reporting a case of a 59-year-old woman, with a family history of breast cancer, who presented with extranodal marginal zone lymphoma (MALT) of the left breast. She received definitive radiation therapy and remains without evidence of disease. Here, we present a case and review the current literature to determine the optimal treatment of this rare presentation of MALT. 

Primary MALT Lymphoma of the Breast Treated with Definitive Radiation.

We compared the clinical outcomes and toxicity profile among a retrospective cohort of patients with primary major salivary gland carcinomas (SGCs) treated with surgery followed by adjuvant radiation therapy (S+RT) versus surgery and adjuvant chemoradiotherapy (S+CRT).

Adjuvant Therapy for Salivary Gland Carcinomas.

We are reporting a case of a 27-year-old woman with a history of swelling in the left submandibular region. This swelling was associated with a mass, and this was pathologically confirmed to be an extranodal marginal zone lymphoma (MALT). The patient underwent surgical excision and postoperative adjuvant radiation therapy. The patient tolerated treatments well and remains free of disease. Here, we describe the case and management described in the current literature.

Radiation for MALT of the Submandibular Gland.

Despite the human papillomavirus conferring a better prognosis in the primary treatment setting, the prognostic impact of viral status after treatment failure in oropharyngeal squamous cell carcinoma patients is poorly understood.

The prognostic impact of human papillomavirus status following treatment failure in oropharyngeal cancer.

We are reporting the case of a 58-year-old woman with history of bilateral silicone breast implants for cosmetic augmentation. At 2-year interval from receiving the breast implants, she presented with swelling of the right breast with associated chest wall mass, effusion around the implant, and axillary lymphadenopathy. Pathology confirmed breast implant-associated anaplastic large cell lymphoma (stage III, T4N2M0, using BIA-ALCL TNM staging and stage IIAE, using Ann-Arbor staging). The patient underwent bilateral capsulectomy and right partial mastectomy with excision of the right breast mass and received adjuvant CHOP chemotherapy and radiation to the right breast and regional nodes. Since completion of multimodality therapy, the patient has sustained remission on both clinical exam and PET/CT scan. We report this case and review of the literature on this rare form of lymphoma.

Article	Year
Radiation therapy for leukemia cutis. Practical radiation oncology\| PubMed ID: 24673948	2011
GFRα1 released by nerves enhances cancer cell perineural invasion through GDNF-RET signaling. Proceedings of the National Academy of Sciences of the United States of America\| PubMed ID: 24778213	2014
The chemokine (CCL2-CCR2) signaling axis mediates perineural invasion. Molecular cancer research : MCR\| PubMed ID: 25312961	2015
A contouring guide for head and neck cancers with perineural invasion. Practical radiation oncology\| PubMed ID: 25407876	2014
A Case of a Laryngeal MALT Lymphoma in a Patient with a History of Gastric MALT. Case reports in hematology\| PubMed ID: 25664189	2015
A unique presentation of occult primary breast cancer with a review of the literature. Case reports in oncological medicine\| PubMed ID: 25866689	2015
Lhermitte's Sign following VMAT-Based Head and Neck Radiation-Insights into Mechanism. PloS one\| PubMed ID: 26448647	2015
Radiographic Thrombus within the External Jugular Vein: Report of a Rare Case and Review of the Literature. Case reports in radiology\| PubMed ID: 26550513	2015
Schwann cells induce cancer cell dispersion and invasion. The Journal of clinical investigation\| PubMed ID: 26999607	2016
Mechanisms of Perineural Invasion. Journal of neurological surgery. Part B, Skull base\| PubMed ID: 27123385	2016
Primary MALT Lymphoma of the Breast Treated with Definitive Radiation. Case reports in hematology\| PubMed ID: 27247809	2016
Adjuvant Therapy for Salivary Gland Carcinomas. Anticancer research\| PubMed ID: 27466526	2016
Radiation for MALT of the Submandibular Gland. Case reports in hematology\| PubMed ID: 28163943	2017
The prognostic impact of human papillomavirus status following treatment failure in oropharyngeal cancer. PloS one\| PubMed ID: 28732044	2017
Breast Implant-Associated Anaplastic Large Cell Lymphoma: Case Report and Review of the Literature. Case reports in hematology\| PubMed ID: 29607225	2018

Richard L. Bakst

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