The Role of ECM Remodeling, EMT, and Adhesion Molecules in Cancerous Neural Invasion: Changing Perspectives

Abstract

the nerve, is often used synonymously with the term PNI. It is important to differentiate between these two terms as the former can be determined using imaging techniques as it is apparent both clinically and radiologically whereas the latter is more of a histological diagnosis. [4,5] The presence of PNI in malignant neoplasms serves as a marker for poor clinical prognosis and higher mortality rate among patients. PNI is most commonly detected in the aggressive pancreatic, prostate, head and neck, colorectal and gastric cancers. [6] Importantly, in some of these cancers, PNI is the only method of metastasis and it can exist independently without vascular and lymphatic invasion. [2,7] In head and neck, the prevalence of PNI varies between 25-80% when compared to non-PNI cases, whereas in pancreatic cancer, 90% of patients exhibit PNI. [8,9] Furthermore, multiple population-based studies carried out over the years have reported no significant difference in the development of PNI based on age, gender, ethnicity/race or other demographic risk factors like smoking history. [10,11,12] Knowledge of the structure and composition of the nerve and its perineural niche is integral to understanding PNI. The peripheral nerves are primarily composed of Schwann cells, fibroblasts, blood vessels along with axon bundles. The Schwann cells are essential for the maintenance of the axons as well as for the production of myelin in the peripheral nervous system. [13] The innermost endoneurium is composed of the extracellular matrix (ECM), fibroblasts and collagen. It is a delicate layer of connective tissue which wraps around the axon and capillaries. The axons are supported and protected by endoneurial cells which are found in this layer. [14] The perineurium has one or more layers of flat epithelial-like cells which group the axons and endoneurium into fascicles. The presence of tight and adherens junctions (AJs) in the epithelial layer adds to the robustness of this layer thereby providing a permeable, but selective barrier between the surrounding axons and tissues. [15] And finally, the outermost epineurium consists of a dense connective tissue layer composed of elastin fibers and collagen which surround the entire nerve bundle. [16] Numerous blood vessels can also be found in this layer as they serve as the vascular supply to the nerve. Based on the structure of the nerve, Leibig et al. [17] combined past and present definitions and defined PNI as the presence of cancer cells along the nerves Perineural invasion (PNI) refers to the cancerous invasion of nerves. It provides an alternative route for metastatic invasion and can exist independently in the absence of lymphatic or vascular invasion.It is a prominent characteristic of specific aggressive malignancies where it correlates with poor prognosis. The clinical significance of PNI is widely recognized despite a lack of understanding of the molecular mechanisms underlying its pathogenesis. The interaction between the nerve and the cancer cells is the most pivotal PNI step which...

Transcriptional subtypes of glottic cancer characterized by differential activation of canonical oncogenic programming

“…29 Moreover, EMT programming has been associated with higher risk of PNI, a disease parameter correlated with State 2 membership and with poorer prognosis among patients with head and neck cancer. 30 However, in this study, we demonstrate the presence of a specific transcriptional subtype of largely locally advanced glottic tumors (T3/T4) wherein the dominant transcriptional phenotype corresponded to EMT signaling. Though a comprehensive discussion of EMT is well beyond the scope of this analysis, therapies including modified synthetic miRNAs to interfere with EMT transcription factors; therapies promoting re-differentiation or trans-differentiation of tumor cells (i.e., mesenchymal-to-epithelial transition [MET]); and, inhibitors or ligand-neutralizing antibodies blocking upstream signaling pathways (e.g., TGF-β, NF-kB), have been explored as modalities for tumors demonstrating an EMT spectrum phenotype.…”

“…In fact, studies investigating immunohistochemical markers in glottic and supraglottic squamous cell carcinoma have correlated both partial‐EMT and EMT with worse overall and disease‐free survival 29 . Moreover, EMT programming has been associated with higher risk of PNI, a disease parameter correlated with State 2 membership and with poorer prognosis among patients with head and neck cancer 30 . However, in this study, we demonstrate the presence of a specific transcriptional subtype of largely locally advanced glottic tumors (T3/T4) wherein the dominant transcriptional phenotype corresponded to EMT signaling.…”

Dysregulation of core neurodevelopmental pathways—a common feature of cancers with perineural invasion

“…Supporting the role of the ECM in nerve–tumor interactions, ECM molecules have been shown to be dysregulated in a transcriptomic analysis of HNSCC comparing samples with clinical PNI to control and non-PNI tumors ( Eviston et al, 2021 ). Several studies have associated ECM molecules with PNI ( Mukherjee et al, 2022 ). For example, laminin 5 was reported to be overexpressed in HNSCC specimens and significantly correlated with the presence of PNI ( Anderson et al, 2001 ).…”

LZTR1 deficiency exerts high metastatic potential by enhancing sensitivity to EMT induction and controlling KLHL12-mediated collagen secretion

“…6 ). Cancer metastasis involves multiple steps, including the closely related EMT induction and ECM remodeling [ 42 ]. In the analysis of EMT induction, LZTR1 deficiency significantly increased the expression of various EMT markers including SLUG and SNAIL.…”