Strategies for Efficient Targeting of Tumor Collagen for Cancer Therapy

Abstract

The tumor stroma, which comprises stromal cells and non-cellular elements, is a critical component of the tumor microenvironment (TME). The dynamic interactions between the tumor cells and the stroma may promote tumor progression and metastasis and dictate resistance to established cancer therapies. Therefore, novel antitumor approaches should combine anticancer and anti-stroma strategies targeting dysregulated tumor extracellular matrix (ECM). ECM remodeling is a hallmark of solid tumors, leading to extensive biochemical and biomechanical changes, affecting cell signaling and tumor tissue three-dimensional architecture. Increased deposition of fibrillar collagen is the most distinctive alteration of the tumor ECM. Consequently, several anticancer therapeutic strategies have been developed to reduce excessive tumor collagen deposition. Herein, we provide an overview of the current advances and challenges of the main approaches aiming at tumor collagen normalization, which include targeted anticancer drug delivery, promotion of degradation, modulation of structure and biosynthesis of collagen, and targeting cancer-associated fibroblasts, which are the major extracellular matrix producers.

Colorectal Cancer Bioengineered Microtissues as a Model to Replicate Tumor-ECM Crosstalk and Assess Drug Delivery Systems In Vitro

“…According to the literature, we reported that the same concentration of AA does not interfere with the cancer cell viability in the 3D CRC Day4 µTs with AA [ 27 ], which also allowed for an increase in ECM production by day 12 of culturing. Since it is known that tumor ECM synthesis increases and collagen fibers are upregulated in several types of cancer [ 28 ], we hypothesized that the significant increase in the collagen synthesis by day 12 of culturing was due to cancer cells that act on continuous ECM remodeling to create a microenvironment that promotes tumorigenesis [ 29 ]. Then, we compared the 3D CRC Day4 µTs with AA to the 3D HCT-116 µTs and 3D Stroma µT monocultures, which were considered controls of cancer cell proliferation and ECM remodeling.…”

Crosstalk between T lymphocyte and extracellular matrix in tumor microenvironment

“…Recent studies indicate that collagen directly contributes to resistance to immune checkpoint inhibitors (ICIs), therefore, targeting collagen may be a potential strategy to improve the efficacy of tumor immunotherapy ( 72 , 102 ) ( 103 – 105 ). Strategies targeting the ECM, particularly collagen proteins, have been proposed in combination with immune checkpoint inhibitors, showing enhanced efficacy at least in murine models ( 106 ). LOX is a key inducer of ECM rigidity, inhibition of LOX enzyme activity, combined with anti-PD-1 administration, improved the infiltration and accumulation of effector CD8+ T cells within tumors and increased the efficacy of PD-1 blockade in a PDAC mouse model ( 8 ).…”

“…Horn and colleagues assessed the combined inhibition of TGF-β, PD-L1, and LAIR-1 signals in a cancer mouse tumor model. This strategy reduced collagen content in the ECM, enhanced infiltration of activated CD8+ T cells, and decreased tumor growth ( 70 , 106 ). The composition and organization of tumor ECM impact drug delivery to tumor cells ( 136 , 137 ).…”

“…Engineering CAR-T cells to express the gene encoding heparanase (HPSE) has been shown to promote T cell infiltration, thus demonstrating antitumor efficacy against matrix-rich solid tumors ( 98 , 143 ). Fibroblast activation protein (FAP), a membrane-bound protease, targeted by CAR-T cells, effectively enhances the killing of tumor cells in vitro and is considered a suitable target for CAR-T cell therapy against immune-suppressive TME components ( 106 , 144 ). Preliminary data from a Phase I clinical trial targeting FAP using CAR T cells for treating mesothelioma suggest the feasibility of this approach ( 106 , 145 ).…”

Long-term cultures of human pancreatic islets in self-assembling peptides hydrogels

“…Tumor-ECM is more abundant, condensed, and stiffer than the ECM in the surrounding healthy tissue. Moreover, oriented collagen fibers around tumor cells, identification of specific collagen organization patterns and evaluation of collagen-associated biomarkers are indicators of tumor progression (Baldari et al, 2022;Song et al, 2022).…”