Abstract
The hallmark of tumours is the ability of cancerous cells to promote vascular growth, to disseminate and invade to distant organs. The metastatic process is heavily influenced by the extracellular matrix (ECM) density and composition of the surrounding tumour microenvironment. These microenvironmental cues, which include hypoxia, also regulate the angiogenic processes within a tumour, facilitating the spread of cancer cells. We engineered compartmentalized biomimetic colorectal tumouroids with stromal surrounds that comprised a range of ECM densities, composition and stromal cell populations. Recapitulating tissue ECM composition and stromal cell composition enhanced cancer cell invasion. Manipulation of ECM density was associated with an altered migration pattern from glandular buds (cellular aggregates) to epithelial cell sheets. Laminin appeared to be a critical component in regulating endothelial cell morphology and vascular network formation. Interestingly, the disruption of vascular networks by cancer cells was driven by changes in expression of several anti-angiogenic genes. Cancer cells cultured in our biomimetic tumouroids exhibited intratumoural heterogeneity that was associated with increased tumour invasion into the stroma. These findings demonstrate that our 3D in vitro tumour model exhibits biomimetic attributes that may permit their use in studying microenvironment clues of tumour progression and angiogenesis.
Highlights
Despite the significant advancements in early diagnostic and therapeutic regimens, the metastatic progression of tumours is the leading cause of mortality in colorectal cancer patients[1]
We have described the development of a 3D in vitro tumour model with controllable parameters including extracellular matrix (ECM) density and composition of the tumour and stroma
While cell migration is a highly coordinated process, we have shown that in the in vitro setting, it is highly dependent on ECM composition over ECM density
Summary
Despite the significant advancements in early diagnostic and therapeutic regimens, the metastatic progression of tumours is the leading cause of mortality in colorectal cancer patients[1]. Natural scaffolds are composed of ECM components that make up an interlocking mesh of fibrous proteins and glycosaminoglycans (GAGs) including collagens, fibrin and hyaluronic acid[6,7]. They provide tissues and cells with mechanical stability and enable cell-matrix interactions to regulate normal tissue function. When used for in vitro 3D cell culture, these scaffolds exist as cross-linked networks of ECM proteins known as hydrogels. One of their main disadvantages is their high water content (upwards of 99%), they are still extremely useful for mechanistic investigations as they are entirely malleable by cell behaviour and subject to cell mediated ECM degradation. The current work presented here focuses on developing more biomimetic tumour models, which incorporate important aspects of the tumour microenvironment that hopefully will shed light on novel mechanisms involved in cancer progression
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