Abnormal Extracellular Matrix as a Hallmark of Cancer
Hayden Byram
The extracellular matrix plays a large role in the formation and progression of cancer. The local environment, or the niche, has been implicated to play a part in this. A major component of the niche is the extracellular matrix (ECM). The ECM is tightly controlled during embryonic development and organ homeostasis. However, it becomes deregulated and disorganized in cancer.
How Does the ECM Promote Cancer?
To answer this question, it is important to understand the various functions of the ECM. To discover the many roles that the ECM can have, review the ECM here.
ECM remodeling is tightly regulated during development. This regulation is carried out by ECM modifying enzymes. However, these enzymes become deregulated with age and disease. Subsequently, the ECM dynamics become abnormal. Stromal cells, cancer-associated fibroblasts, and immune cells contribute to the altered activity of the ECM remodeling enzymes.
The abnormal dynamics of the ECM are well documented in cancer cases. Various collagens show increased deposition during tumor formation. It has been observed that ECM components and their receptors are often overproduced in cancer. There are also notable differences in in the stroma. Tumor stroma is typically stiffer than normal stroma. In breast cancer, the tissue can be up to ten times stiffer than that of normal breast cancer.
Under normal circumstances, the ECM maintains tissue polarity and prevents cancer cell invasion. Epithelial cells have distinct polarity needed for organ formation and function. However, this is typically lost in cancer. For example, beta-1-integrin usually maintains tissue polarity in solid organs such as the mammary gland, but will lose this ability in cancer. For more information of how cancer can affect cell polarity, see Lee and Vasioukhin 2008.
Inflammation plays a causative role in cancer development. It has been noted that the ECM can affect tumor-associated inflammation. Initially immune cells suppress tumor growth. However, at the later stages of cancer, immune cells can be altered and recruited to promote cancer. In fact, and abnormal ECM affects many aspects of immune cell behavior, such as infiltration, differentiation, and functional activation.
Lu et al. 2012 did a study that helped show how the ECM can affect the immune system and lead to an increase in cancer. They studied mice lacking the ECM glycoprotein SPARC. This mice secreted protein that was acidic and rich in cysteine. They also noticed an increased number of macrophages in tumors, leading them to the conclusion that the ECM can influence the number of immune cells.
Lu et al. 2012 provided this image, giving a detailed overview of how an abnormal ECM can promote cancer. See the article for more information.
Focal Adhesions
Focal adhesions are dynamic protein complexes that connect the cytoskeleton of a cell the the ECM. They are in a state of constant flux, with proteins associating and dissociating continuously as signals are transmitted to other parts of the cell. This complex can contain over 100 different proteins.
The focal adhesions have many different functions. They provide anchorage for the cell, can be signal carries or sensors, and inform the cell about the condition of the ECM, thus affecting behavior of the ECM. Mechanical force and regulatory signals are also transmitted through focal adhesions.
The focal adhesion's connection to the ECM involves the protein integrin. Integrin binds to extracellular proteins via short amino acid sequences. The intracellular domain of integrin binds to the cytoskeleton via adapter proteins such as talin, filamin, and vinculin.
The following is a good video giving an overview of focal adhesions.
Focal Adhesion Kinase
Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase residing at focal adhesion sites. It is an important mediator of cell adhesion, growth, proliferation, survival, angiogenesis, and migration, all of which can be disrupted in cancer. FAK is a key mediator of signaling by integrins, and can trigger multiple intracellular signaling pathways to regulate various cellular functions. However, FAK can promote tumorigenesis through phosphorylation. It has been discovered that FAK plays a prominent role in tumor progression and metastasis.
Normally, FAK levels are low in healthy tissues. However, over expression and activation of FAK have been found in a variety of human cancers. For this reason, small molecule inhibitors of FAK have been developed and are being tested as a treatment for cancer. See Golubovskaya 2010 for more information.
Focal Adhesion Kinase as a Cancer Therapy Target
Since focal adhesion kinase has been discovered to play a role in the progression of cancer, it is not surprising that drugs are now being used to target FAK in order to treat cancer. Golubovskaya 2010 published an article summarizing some of the major studies targeting FAK for cancer treatment. See this article to discover the many different ways that drugs such as TAE226, a FAK molecule inhibitor, can be used to promote apoptosis in breast cancer cells, and learn about the various other treatment options for a wide range of cancers. A few of these techniques are summarized below.
Since focal adhesion kinase was significantly elevated in breast tumors, Golubovskaya 2010 used a FAK inhibitor, TAE226, to induce apoptosis in breast cancer cells. A similar process was used in the treatment of Neuroblastoma. The same FAK inhibitor, TAE226, caused apoptosis in the neuroblastoma cells. Inhibition of FAK with FAKsiRNA also inhibited metastasis in a nude mouse model. Furthermore, Troglitazone was successful in inhibiting cancer cell motility in ovarian and cervical cancers as well.
Since focal adhesion kinase was significantly elevated in breast tumors, Golubovskaya 2010 used a FAK inhibitor, TAE226, to induce apoptosis in breast cancer cells. A similar process was used in the treatment of Neuroblastoma. The same FAK inhibitor, TAE226, caused apoptosis in the neuroblastoma cells. Inhibition of FAK with FAKsiRNA also inhibited metastasis in a nude mouse model. Furthermore, Troglitazone was successful in inhibiting cancer cell motility in ovarian and cervical cancers as well.
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