Improving cancer therapies by targeting the physical and chemical hallmarks of the tumor microenvironment

Abstract

Tumors are highly heterogeneous at the patient, tissue, cellular, and molecular levels. This multi-scale heterogeneity poses significant challenges for effective therapies, which ideally must not only distinguish between tumorous and healthy tissue, but also fully address the wide variety of tumorous sub-clones. Commonly used therapies either leverage a biological phenotype of cancer cells (e.g. high rate of proliferation) or indiscriminately kill all the cells present in a targeted volume. Tumor microenvironment (TME) targeting represents a promising therapeutic direction, because a number of TME hallmarks are conserved across different tumor types, despite the underlying genetic heterogeneity. Historically, TME targeting has largely focused on the cells that support tumor growth (e.g. vascular endothelial cells). However, by viewing the intrinsic physical and chemical alterations in the TME as additional therapeutic opportunities rather than barriers, a new class of TME-inspired treatments has great promise to complement or replace existing therapeutic strategies. In this review we summarize the physical and chemical hallmarks of the TME, and discuss how these tumor characteristics either currently are, or may ultimately be targeted to improve cancer therapies.

Keywords: Chemcical tumor microenvironment; Electroporation therapy; Physical tumor microenvironment; Tumor microenvironment targeting.

Figure 1

Major alterations in the mechanical tumor microenvironment. a) The rapid proliferation of cancer cells and stromal cells along with the deposition of collagen creates solid forces within the tumor. These forces cause compression of blood vessels, which leads to areas of high interstitial fluid pressure in the tumor [22]. b) A comparison of the interstitial fluid pressure in aggregated data collected from a variety of human tumors as compared to normal human tissues shows an often drastic increase in IFP in the tumor microenvironment [29]. Data was collected from human patients using the wick-in-needle technique for measurement.

Figure 2

Irreversible electroporation from in vitro to in vivo (a) visualization of live/dead cells after IRE treatment in a 3D in vitro tumor model [101], (b) Sparing of major blood vessels after IRE treatment of canine brain [102], (c) Delineation between viable tissue (left) and reactive fibrosis and hemorrhage (right) is seen in human prostate IRE histology, adapted from [103], (d) 7.0-T MRI of IRE-treated canine brain, adapted from [104], (e) dual probe insertion during the intracranial IRE procedure in canine brain [102] Owing to their short rise time which is faster than cell membrane charging time, nanosecond pulsed electric fields (nsPEFs) penetrate the cell membrane and damage intracellular structures, with minimal membrane electroporation [105, 106]. In vitro studies on skin cells have shown that tumor cells have a stronger response to nsPEFs than normal cells [107, 108], and suggest that an improved understanding of the electrical differences among cells may lead to more targeted therapies based on exploiting these differences.

Figure 3

TME-inspired therapies (outer rings) in different stages of development or translation, and their relation to the physical and chemical hallmarks targeted (inner)