In vitro 3D modeling of colorectal cancer: the pivotal role of the extracellular matrix, stroma and immune modulation

Abstract

Colorectal cancer (CRC) is a leading global cancer with high mortality, especially in metastatic cases, with limited therapeutic options. The tumor microenvironment (TME), a network comprising various immune cells, stromal cells and extracellular (ECM) components plays a crucial role in influencing tumor progression and therapy outcome. The genetic heterogeneity of CRC and the complex TME complicates the development of effective, personalized treatment strategies. The prognosis has slowly improved during the past decades, but metastatic CRC (mCRC) is common among patients and is still associated with low survival. The therapeutic options for CRC differ from those for mCRC and include surgery (mostly for CRC), chemotherapy, growth factor receptor signaling pathway targeting, as well as immunotherapy. Malignant CRC cells are established in the TME, which varies depending on the primary or metastatic site. Herein, we review the role and interactions of several ECM components in 3D models of CRC and mCRC tumor cells, with an emphasis on how the TME affects tumor growth and treatment. This comprehensive summary provides support for the development of 3D models that mimic the interactions within the TME, which will be essential for the development of novel anticancer therapies.

Keywords: 3D model; colorectal cancer; extracellular matrix; immune cells; in vitro; therapy; tumor microenvironment.

FIGURE 1

CRC development and transformation in different stages from adenomatous polyps to metastases. Four stages in the development of CRC carcinogenesis occur: initiation, promotion, progression, and metastasis. The most common metastatic site is the liver, followed by the lung and bone. Created with BioRender.com.

FIGURE 2

CRC are divided into four different groups based on the consensus molecular subtypes. The first group is characterized by MSI, high mutations of BRAF and activated immune components. The second involves epithelial differentiation and MYC mutations, causing high activity of these intracellular signaling pathways. It also features increased expression of EGFR, TP53 and APC. The third group shows metabolic dysregulation with increased activity in glutaminolysis and lipidogenesis, enriched with KRAS activating mutations. The fourth group show the expression of genes related to stromal invasion, epithelial–mesenchymal transition (EMT), transforming growth factor-beta (TGF-β), and angiogenesis. Created with BioRender.com.

FIGURE 3

3D models mimicking the TME of CRC and mCRC compartments. A complex network of cellular and ECM microenvironmental interactions is critical for cancer progression, and is essential not only for the primary CRC tumor, but also for the metastatic scenario. Except for the immune and stromal cells, liver sinusoidal endothelial cells, Kupffer cells and other liver macrophages are necessary for maintaining the mCRC tissue environment in the liver. Created with BioRender.com.

FIGURE 4

Stromal cell compartment is a complex key environment surrounding the cancer cells, consisting of MSCs, fibroblasts, and endothelial cells. Created with BioRender.com.

FIGURE 5

Interaction between CRC and TAMs. Different stimuli can polarize macrophages into two basic types, anti-tumorigenic M1 and pro-tumorigenic M2 phenotypes. M1 macrophages can be stimulated by interferon IFN-γ and express inflammatory factors including interleukin IL-1β, IL-6, and tumor necrosis factor TNF-α. M2 macrophages are stimulated by IL-4 and IL-13 and express IL-10 and transforming growth factor TGF-β, among other cytokines. Created with BioRender.com.