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Brown. Rare Dis Orphan Drugs J. 2025;4:21 https://dx.doi.org/10.20517/rdodj.2025.14 Page 5 of 15

human lifespan if not actively degraded by Schwann cells and fibroblasts, blocks immune cell migration and
drug diffusion, and induces pro-tumorigenic signaling.

The collagenolysis of COLVI is not yet fully understood; however, matrix metalloproteases (MMPs) 2, 7, 9,
[23]
11, and 14 are able to digest moieties . The major anabolic machinery for collagen resides within the cell
cytoplasm. Collagens bind to integrin proteins at the cell membrane and a small peptide moiety is cleaved,
which signals macro-pinocytosis, clathrin-mediated phagocytosis, or endocytosis of fragments released by
MMPs, followed by cathepsin-mediated lysosomal digestion. COLIV exists as a heterotrimeric helix
composed of six interchangeable isomeric subunits. When excreted, COLIV self-organizes into irregular
hexagonal networks of tetramers or rope-like dimers that are stabilized through hydrophobic/hydrophilic
interactions as well as a lock-in-key mechanism wherein conjugate beta hairpin structures plug into
neighboring carboxy terminal domains.

In addition to providing structure and altering diffusion characteristics, ECM contributes to the tumor
microenvironment by binding to cell surface proteins to enact diverse pro-tumorigenic signaling pathways
within both stromal and tumor-associated NF1 heterozygous cells. COLVI binds to neural/glial antigen 2
(NG2), integrins, or the capillary morphogenesis gene 2 (CMG2/ANTXR2) receptor and activates the cyclic
AMP response element-binding protein (CREB)/AKT/β-catenin/T cell factor/lymphoid enhancer factor
[24]
pathway (TCF-LEF) and phosphatidylinositol-3 kinase (PI3K) signaling . The C-terminal of COLVI
[20]
(A3) can be proteolytically cleaved, releasing the signaling factor endotrophin, which promotes fibrosis and
inflammation. COLVI ultrastructurally interacts with biglycan, fibronectin, decorin, von Willebrand factor
(vWF), vWF-A domain-related protein (WARP), fibulin, heparin sulfate, and other collagens, notably COLI
and COLIV. COLVI is implicated in the inhibition of apoptosis, the maintenance of a stem-like quality, the
[25]
promotion of tumor growth, and the activation of autophagy .

COLIV is less well-studied than COLVI in tumor biology. It has been proposed as an inducer of
epithelial-mesenchymal transition, potentially heralding a poorer prognosis in certain cancers . COLIV
[26]
has a known specificity for binding tumor cells and encouraging migration along the collagenous matrix.
This interaction relies on integrin α β signaling at an ultrastructural binding site that includes arginine 461
1 1
in the alpha 2 subchain and asparagine 461 within the alpha 1 subchain. COLIV also binds to laminins,
perlecan, and proteoglycans. Non-integrin binding mechanisms occur through cell-surface proteins CD44,
discoidin domain receptors (DDRs), heparin sulfate proteoglycans, glycoprotein VI, and the mannose
receptor family. Injection of COLIV into the rat sciatic nerve in an in vivo injury model induced cellular
proliferation, fibroblast immigration, and neurite extension, although it did not induce Schwann cell
mitosis . COLIV may facilitate nerve regeneration, although the mechanism likely does not involve
[27]
Schwann cell activation.

Hyaluronic acid and collagen deposition are associated with high tumor interstitial pressure, low oxygen
tension, microvascular collapse, and hypoxia signaling in tumor cells , and collagen density correlates
[28]
negatively with T cell migration into tumors and positively with macrophage-dependent
immunosuppression . The overall effect of this dense irregular ECM deposition is to block drug diffusion
[29]
and immune cell migration, reduce glucose and oxygen supply, increase drug efflux via hypoxia inducible
factor 1α (HIF-1α), increase survival (integrins), and reduce cell cycle arrest via FAK signaling . Through
[20]
these downstream ECM-activated pathways, particularly COLVI, resistance has been documented in solid
tumors to multiple targeted and chemotherapeutic agents. ECM-targeted drug co-administration may
[30]
provide a means to increase the efficacy of MEK inhibitors and other targeted therapies for CNs .