Towards extracellular matrix normalization for improved treatment of solid tumors

Abstract

It is currently challenging to eradicate cancer. In the case of solid tumors, the dense and aberrant extracellular matrix (ECM) is a major contributor to the heterogeneous distribution of small molecule drugs and nano-formulations, which makes certain areas of the tumor difficult to treat. As such, much research is devoted to characterizing this matrix and devising strategies to modify its properties as a means to facilitate the improved penetration of drugs and their nano-formulations. This contribution presents the current state of knowledge on the composition of normal ECM and changes to ECM that occur during the pathological progression of cancer. It also includes discussion of strategies designed to modify the composition/properties of the ECM as a means to enhance the penetration and transport of drugs and nano-formulations within solid tumors. Moreover, a discussion of approaches to image the ECM, as well as ways to monitor changes in the ECM as a function of time are presented, as these are important for the implementation of ECM-modifying strategies within therapeutic interventions. Overall, considering the complexity of the ECM, its variability within different tissues, and the multiple pathways by which homeostasis is maintained (both in normal and malignant tissues), the available literature - while promising - suggests that improved monitoring of ECM remodeling in vivo is needed to harness the described strategies to their full potential, and match them with an appropriate chemotherapy regimen.

Keywords: collagen; fibrosis; hyaluronic acid; nano-formulations; tumor extracellular matrix.

Figure 1

Towards extracellular matrix (ECM) normalization for improved treatment of solid tumors. Healthy ECM versus aberrant tumor ECM (left and right panels, respectively). Healthy ECM is characterized by the presence of an intact basement membrane, non-activated fibroblasts and random arrangement of collagen fibers (left panel). Aberrant tumor ECM features the tumor vessel basement membrane with a heterogeneous thickness that allows the dissemination of tumor cells as well as accumulation of nano-formulations. The presence of collagen fibers which are aligned in an ordered fashion and activated fibroblasts are other characteristics of tumor ECM.

Figure 2

Fibroblasts are highly plastic and exhibit multi-potency. Activated fibroblasts readily differentiate into adipocytes, chondrocytes and endothelial cells, among others. Adapted with permission from , Copyright 2016 Springer Nature. Of note, there are conflicting reports on the differentiation of activated fibroblasts into adipocytes .

Figure 3

Molecular processes involved in wound repair and fibrosis. LOX: lysyl oxidase, LOXL2: lysyl oxidase like 2, MMP: matrix metalloproteinase, PDGF: platelet-derived growth factor, and TGF-β: transforming growth factor beta. Adapted with permission from , Copyright 2007 American Society for Clinical Investigation.

Figure 4

Interactions of tumor-associated fibroblasts and collagen. Daily multiphoton laser scanning microscopy images were acquired in a tumor growing in a dorsal skinfold window chamber. Two channels were acquired: Second harmonic generation (SHG) signal arising from collagen (shown in red), and green fluorescent protein (GFP) present in cancer associated fibroblasts (shown in green). Image montage presents a maximum intensity projection of a few images each, acquired 24 hours apart for four consecutive days. Fibroblasts are seen to migrate within the tumor to varying degrees, and occasionally interact with collagen fibers. Figure is generated from data provided by Dr. Trevor D. McKee which was originally captured and analyzed in . With permission from , Copyright 2009 Springer Nature.

Figure 5

Fibrosis in cancer. Representative trichrome (blue) staining for collagen in normal pancreas and different cancerous tissues. Magnification ×20. Reprinted with permission from , Copyright 2017 Springer Nature.

Figure 6

Heat-triggered intravascular drug release from thermosensitive liposomes. Localized mild hyperthermia is employed to heat the tumor area by a few degrees (39-43°C) which can trigger rapid drug release within the tumor microvasculature. The released drug enters the tumor interstitium via diffusion along the existing concentration gradient.

Figure 7

Schematic model of therapeutic interventions for normalization of the extracellular matrix (ECM) in solid tumors.