Response to acute severe and chronic
liver injury. Understanding the molecular mechanisms whereby cell-matrix
interactions regulate liver regeneration may allow novel strategies to enhance
this process. Both the ductular reaction in humans and hepatic progenitor cells
in rodent models are closely associated with collagen and laminin, although
there is still debate about cause and effect. Recent studies have shown a
requirement for matrix remodeling by matrix metalloproteinases for the
proliferation of hepatic progenitor cells and suggested defined roles for
specific matrix components. Understanding the interactions between progenitor
cells and matrix is critical for the development of novel regenerative and
antifibrotic therapies.
Matrix changes and signaling in the
HPC niche. The components of the HPC niche during both biliary and hepatocytic
regeneration are shown. Hepatic stellate cells (HSCs Interactions between cells
and their extracellular matrix have been shown to be crucial in a wide range of
biological processes, including the proliferation and differentiation of stem
cells. Ductular reactions containing both hepatic progenitor cells and
extracellular matrix are seen in) and collagen are associated with HPCs in
biliary regeneration and macrophages (Mφ) with hepatocytic regeneration. A
laminin-containing basement membrane is closely associated with HPCs in both
processes. Although these 2 processes are shown separately for clarity, they
may occur simultaneously during liver injury. In addition to altering the
matrix, hepatic stellate cells and macrophages can send signals directly to, and
receive signals from, HPCs. Candidate pathways that may either drive changes in
matrix deposition and degradation or occur in parallel with these changes are
shown. CTGF, connective tissue growth factor; EGF, epidermal growth factor;
HGF, hepatocyte growth factor; HH, hedgehog; IGF, insulin-like growth factor;
MCP-1, monocyte chemotactic protein 1; PDGF, platelet-derived growth factor;
TIMP, tissue inhibitor of metalloproteinase; VEGF, vascular endothelial growth
factor.
Obesity-induced factors contribute
to colorectal carcinogenesis. Mechanisms by which obesity could contribute to
development of CRC are shown. Western-style diets lead to increased adiposity
and changes in the microbiota to adapt to the increased energy supply.
Adipokines such as leptin and adiponectin could allow for establishment of a
tumor microenvironment. In obese subjects, hyperlipidemia and insulin resistance
lead to low-grade systemic inflammation, which promotes tumor cell
proliferation and angiogenesis and reduces apoptosis. These mechanisms are
likely to vary among subjects, and little is known about their interactions.
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