Extracellular Matrix Targets in Cancer Therapy

“The human form is at once a circle and a square. Both curve and straight line, they enclose and define a universe both infinite and finite, spiritual and material.” – Leonardo da Vinci Leonardo da Vinci’s words highlight the dual essence of the extracellular matrix (ECM) in cancer treatment. The ECM is both complex and offers a key opportunity in treating cancer.

tumor microenvironment

The ECM creates a framework for the tumor environment. It not only supports structurally but also shapes the actions of cancer cells. Changes in the ECM cause tissues to become stiffer, which helps cancer cells grow and spread. For example, in mammals, there are about 300 ECM components. These vastly influence how cancer grows and spreads by affecting around 1000 genes.

Dealing with these ECM changes is a crucial area for new cancer treatments. Doing this lets scientists look into how ECM parts work in normal and cancerous conditions. It also opens the door to study how cancer cells and the ECM interact, and the changes in receptors that sense mechanical forces.

Excessive ECM buildup, called desmoplasia, is a key feature of aggressive tumors. These include types like pancreatic, breast, and ovarian cancers, usually leading to poor results from treatments. Conditions with such buildup, like liver cirrhosis, also increase cancer risk. Bringing in treatments that focus on the ECM could better stop cancer growth and improve patient results.

New cancer treatments are now focusing on the ECM by either targeting specific ECM parts or changing the ECM itself. Elements like Collagen are becoming key targets in cancer research. For example, more collagen can help start and increase breast cancer. Finding ways to disrupt the tumor’s support structure is an important step towards more successful cancer treatments.

Key Takeaways

The ECM is important for the structure of tumors and affects how cancer cells behave.
Alterations in the ECM can lead to tissue getting stiffer and kickstart cancer.
Stiffening tissue, also known as desmoplasia, often means worse outcomes for patients with aggressive tumors like PDAC and breast cancer¹.
Health problems that involve too much ECM can raise the chance of getting cancer¹.
By focusing on ECM elements such as collagen and fibronectin, new paths for treatment open up.

Understanding the Extracellular Matrix (ECM)

The extracellular matrix (ECM) is a vital scaffold for tissues and cells. It maintains cell attachment and holds growth factors. This is key for normal function and during diseases like cancer.

Structure and Function of ECM

The ECM is made up of proteins like collagen and elastin, and hyaluronan. Collagen is the most common protein, making up about 90% of the ECM. It shapes tissues and affects how cells act and grow.

Major Components of ECM

The ECM mainly contains collagen, elastin, and hyaluronan. Collagen’s strength comes from its unique structure. Matrix metalloproteinases (MMPs) help break down and rebuild collagen, which is key in cancer growth.

Role in Tissue Homeostasis

The ECM supports tissues, helps with cell attachment, and stores water and growth factors.² It affects cellular behavior, ensuring tissues work properly. By targeting the ECM, we find new ways to fight cancer.

Fibroblasts help make the ECM, especially collagen, leading to desmoplasia in cancers. Too much collagen in tumors makes the ECM stiff. This stiffness changes tissue signals, impacting cancer growth. So, focusing on the ECM is key in developing new cancer treatments.

The Role of ECM in Tumor Microenvironment (TME)

The extracellular matrix (ECM) in the tumor microenvironment (TME) is key in how cancers grow and spread. It talks with cancer and stromal cells, changing how they grow, move, and hide from the immune system.

ECM Interaction with Tumor Cells

The relationship between the extracellular matrix and tumor cells changes over time. Tumor cells tweak the ECM to support their own growth. This tweak involves making more of certain enzymes, causing changes in collagen and making it harder for chemotherapy to work³. Also, the ECM adds more proteoglycans in tumors than in healthy tissue. This spurs on tumor growth and helps them stay alive³.

Stromal Cells and ECM

Stromal cells, like cancer-associated fibroblasts (CAFs), help change the ECM, which changes the tumor’s environment. They play a big role in how tumors reject therapy. In 2018, work by Santi A, and others, showed how important CAFs are in this change⁴. Plus, the ECM helps stromal cells move, aiding the tumor’s advance.

Impact on Tumor Progression

Changes in the ECM greatly affect how tumors grow. In some breast cancers, the type of collagen made switches, making the tumor more aggressive³. The hardening of ECM turns on certain receptors, increasing the danger of tumor and stromal cells. As the ECM makes up such a big part of many tumors, controlling these changes is vital to managing tumor growth³.

ECM Dysregulation and Cancer

Extracellular matrix (ECM) dysregulation is key in cancer growth and spread. This network changes a lot in cancer, making tissues harder and tumors grow faster.

Mechanisms of ECM Alteration in Cancer

Oncogenic pathways change the ECM by affecting protein creation and links. This process creates an ideal space for cancer to spread. Also, how dense the collagen is in tumors affects how our immune cells work in that area*⁵*.

Impact of ECM Stiffness on Tumor Behavior

Many cancers get harder because of more protein links in the ECM. This change triggers certain receptors, leading to more cell growth, movement, and spread. For instance, lung cancer cells move and spread more in a stiffer environment⁶.

By understanding how the ECM changes, we can find ways to slow down cancer. Targeting specific parts of the ECM might lead to new treatments. This approach could help fight the spread and growth of tumors⁵.

Key ECM Components as Therapy Targets

Scientists are looking at the extracellular matrix (ECM) in a new light for fighting cancer. They see collagen, elastin, and hyaluronan as key players. Changes in these elements are linked to the growth and spread of tumors.

Collagen is important in how cancer cells spread and act aggressively. When the ECM gets stiffer, it can also help cancer evade our immune system in breast cancer⁷. Plus, both collagen and fibronectin push breast cancer cells to behave more aggressively⁷. Research also points to the ECM’s role in aging-related cellular stoppage⁷.

Elastin is crucial for keeping tissues stretchy and strong. But, too much or too little of it around a tumor can help the cancer grow and spread⁷. A special protein called elastin microfibril interface located protein 2 influences the tumor environment in different ways⁷.

Hyaluronan helps keep tissues hydrated and is key in how cells communicate. Too much of this molecule is tied to severe types of cancer and bad outcomes. Blocking its production could be a way to slow down cancer spread⁵.

Understanding what ECM components do and how they change due to disease helps us create better therapies. These treatments are focused on fixing the problems that come with ECM changes, ultimately helping in treating cancer better.

ECM Component	Role in Cancer	Potential Therapy Target
Collagen	Invasion, Aggression, ECM Stiffening	Collagenase Nanoparticles⁷
Elastin	Structural Integrity, Inflammatory Response	Elastin Microfibril Protein⁷
Hyaluronan	Hydration, Cellular Signaling	Inhibition of Synthesis Pathways⁵

Collagen: Structure, Function, and Targeting

Collagen is the most common protein in the extracellular matrix (ECM). It helps keep tissues strong and elastic. In cancer, changes in collagen make the ECM rigid. This can help tumors grow.

Role of Collagen in ECM

Studies show collagen can make cancer treatments less effective. It does this by making immune cells too tired to work. Collagen type I also influences how cells behave in tumors. And the amount of collagen affects how well immune cells can fight cancer⁸.

Collagen Modulation in Therapy

Changing how collagen works might be great for treating cancer. By affecting how collagen is made and broken down. A study found that the way collagen fibers are lined up can help cancer spread.

Also, breaking down collagen in the right way affects the outcome of pancreatic cancer⁹. Changing the environment around tumors by targeting specific cells could be a good strategy. It might help stop the cancer from growing⁸.

And there’s another way to target collagen. It’s by using medicines that block DDR1, a protein that’s important for collagen. This might help fight against fibrosis and slow down cancer⁹. Checking for specific collagen pieces in blood could help doctors decide if a certain cancer therapy will work⁸.

Knowing more about collagen in the ECM opens doors for new cancer treatments. Changing collagen’s structure and amount can make the environment less friendly for cancer growth. This approach could be a big win in fighting cancer⁸⁹.

Fibronectin and Its Role in Cancer

Fibronectin is a key protein in the extracellular matrix (ECM). It helps with cell attachment, growth, and healing. But in cancer, fibronectin’s special role is getting more attention due to how it changes in the tumor’s environment.¹⁰

Structure and Biological Function

There are soluble and insoluble forms of fibronectin. It binds to cell receptors like integrins, aiding in cell sticking together and building the matrix. High levels of fibronectin can speed up early tumor growth and spread. This happens because it makes it easier for cells to move and invade other areas.¹⁰ When comparing different tissues, studies have found more fibronectin in cancer areas. This is tied to more aggressive tumors and worse outcomes for patients.¹¹¹⁰

Therapeutic Potential of Targeting Fibronectin

Trying to stop fibronectin from working in cancer treatment is a focus. Efforts are being made to block its connections with integrins. Doing this may slow down important cancer processes like cell move and invasion. It may also reduce the risk of cancer spreading.¹⁰ Recent lab studies have shown that stopping fibronectin in this way can slow down cancer growth and spread. These findings have led to an increase in trials testing such therapies in patients, showing they might be a new way to treat cancer.¹²¹¹

Studies show that fibronectin levels can predict how well cancer patients do. High fibronectin is often seen with bad results in breast, lung, and bowel cancers.¹¹ This highlights the promise of strategies aimed to reduce fibronectin in helping patients do better.

Furthermore, fibronectin plays a big part in older people’s cancer growth. As you age, the environment where cancer grows changes too, because of differences in the ECM. Targeting fibronectin could be a game-changer in how we treat cancer in older adults. It offers a new approach in the battle against cancer.

Elastin’s Contribution to Tumor Microenvironment

Elastin is a key part of the ECM, giving tissues their elasticity. It affects smooth muscle and fibroblasts¹³. In the tumor area, elastin breakdown changes how cells act and triggers inflammation. Studies show elastin helps cancer spread by signaling interactions and encouraging cell movement¹⁴. This breakdown is often found in breast cancer, becoming worse as the disease progresses¹³.

To fight cancer, we need to know how elastin works in the ECM. This knowledge is crucial for new treatments that aim to stop the pathways supporting cancer growth¹⁴. Targeting elastin could block the processes aiding cancer spread, offering hope for better treatments¹³.

Stats show elastin is key in many cancer types, with big impacts on liver and kidney diseases, and breathing issues. It shows how important elastin is in tissue changes and fighting inflammation¹⁴. This data suggests that focusing on the ECM, especially elastin, could slow down cancer and improve treatment results¹⁵.

Elastin-related strategies could open new doors for treating various cancers¹³. By targeting elastin in the ECM, we might make big breakthroughs against cancer¹⁴.

Clinical Insights	Key Findings
Breast Cancer	High elastin degradation correlates with disease severity¹³.
Liver Fibrosis	Accumulation of elastin fibers aids in diagnostic insights¹⁴.
Kidney Fibrosis	Noninvasive elastin imaging assists in staging and monitoring¹⁴.

Hyaluronan: A Key Player in Cancer Progression

Hyaluronan is a major glycosaminoglycan that helps keep tissues hydrated. It also plays key roles in how cells communicate and in changing the environment around them. High levels of hyaluronan have been found in aggressive cancers, often leading to a worse outlook for patients¹⁶¹⁷. Research by Toole et al. in 1979 showed that in rabbit cancer, more hyaluronan meant the cancer was more likely to invade¹⁶. Studies in 2022 by Oliveira-Ferrer and colleagues also suggested that if ovarian cancer cells produce a lot of hyaluronan, it’s not good for the patient’s outcome¹⁶.

Biological Function and Impact

In the body, hyaluronan is important for the extracellular matrix (ECM). This is the environment surrounding our cells. It helps cells move and grow, and makes it easier for tumors to build their own blood supplies. Kimata et al. discovered in 1983 that certain breast cancer cells, which spread a lot, also made more hyaluronan. This finding suggests a link between hyaluronan and the ability of cancers to spread around the body¹⁶. Anttila et al.’s 2000 study found that in ovarian cancer, high levels of hyaluronan around the cancer predicted a worse outcome¹⁶. And Auvinen et al. in the same year noted that in breast cancer, hyaluronan in the tissue around the tumor linked to a worse outcome for the patient¹⁶.

Targeting Hyaluronan in Cancer Therapy

Since hyaluronan is important for cancer growth and spread, blocking it could be a good way to treat cancer. Tammi and others in 2008 pointed out that the amount of hyaluronan around cancer cells was a sign of how well a patient would do. This means treatments aiming to lower hyaluronan might help improve patient outcomes¹⁶. Bourguignon et al. showed in 2009 that a certain connection between hyaluronan and cells in breast cancer made the cancer harder to kill with medicines¹⁶. Simpson et al. in 2012 found that blocking a receptor for hyaluronan stopped prostate cancer from spreading to the lymph nodes¹⁶. Different types of hyaluronan-based treatments might change how cancer cells react and help make them easier to treat with existing medicines¹⁶¹⁷.

Study	Findings
Oliveira-Ferrer et al., 2022	Pericellular hyaluronan deposition by ovarian cancer cells negatively impacts patient prognosis¹⁶
Toole et al., 1979	Correlation between hyaluronate levels and invasiveness in rabbit carcinoma¹⁶
Kimata et al., 1983	Increased hyaluronic acid synthesis in mammary carcinoma cells with high metastatic potential¹⁶
Anttila et al., 2000	High stromal hyaluronan levels predict poor disease outcome in epithelial ovarian cancer¹⁶
Auvinen et al., 2000	Hyaluronan levels in peritumoral stroma linked to breast cancer metastasis and survival prognosis¹⁶
Simpson et al., 2012	Systemic blockade of the hyaluronan receptor prevented lymph node metastasis of prostate cancer¹⁶

As we keep studying hyaluronan, we learn more about how its unique properties affect cancer. This knowledge helps us develop better ways to target and treat cancer with cancer treatment strategies in the future.

Mechanotransduction Pathways in ECM

The extracellular matrix (ECM) is vital in how cells feel and react to physical forces. Key receptors like Integrins, Piezo1, and TRPV4 change these forces into messages that cells use. These messages affect cancer cells, potentially leading to new cancer treatments.

Key Receptors: Integrins, Piezo1, and TRPV4

Integrins help cells stick and move, important in cancer spreading. Nanopatterns that activate integrins can change cell actions, showing their role in the process. Also, Piezo1 and TRPV4 are crucial for feeling force, contributing to cancer’s move¹⁸. In breast cancer, integrins boost the strength cancer cells need to move, making them a target for new treatments¹⁸.

Signaling Pathways Activation

Blocking or changing how ECM pathways work could help fight cancer. These pathways interact with the mechanical environment, affecting cancer growth¹⁸. For instance, activating integrins with specialized surfaces or the mechanics of certain cells can encourage cancer cells to move more¹⁸. Understanding this offers hope for better cancer treatments.

Research suggests we need to look closely at mechanotransduction pathways for new cancer solutions. These pathways don’t just affect cancer cells but also the environment around tumors. This makes them key for future ECM-focused cancer treatments.

FAQ

How does the extracellular matrix (ECM) influence cancer progression?

The ECM is like a building’s frame, keeping things together. It also guides how cancer cells act in their space. Changes in the ECM make tissues hard, which helps cancer cells grow and spread more easily.

What are the major components of the extracellular matrix (ECM) in cancer?

The ECM has key parts like collagen and elastin, giving it structure. Proteins such as fibronectin and hyaluronan help cells stick together, grow, and talk to each other.

What role does ECM stiffness play in tumor behavior?

Stiff ECM can push cancer cells to be more aggressive. It does this by turning on specific proteins on the cell surface. This activation boosts cell growth, spread, and makes cells resist cancer drugs.

How can targeting the extracellular matrix (ECM) be beneficial in cancer therapy?

By aiming at ECM parts like collagen and fibronectin, we can upset how tumors grow. This approach changes how stiff the ECM is and how cancer and healthy cells communicate. It might slow down cancer.

What is the therapeutic potential of targeting collagen in cancer treatment?

Targeting collagen can change how hard the ECM is. It stops signals that support tumor growth. This tactic may offer a new way to fight cancer.

How does fibronectin contribute to cancer and its treatment?

Fibronectin is key in making cells stick together, grow, and move. Too much of it can aid tumor spread. If we can block fibronectin’s work with drugs, we might be able to stop cancer’s growth.

What is the significance of elastin in the tumor microenvironment?

Elastin makes tissues stretchy. In cancer, its leftovers change how cells behave and cause inflammation. Finding ways to stop elastin’s signals might slow down cancer.

What role does hyaluronan play in cancer, and how can it be targeted therapeutically?

Hyaluronan helps keep tissues moist and aids cancer in growing and spreading. We can slow cancer by blocking how hyaluronan works or by lowering its levels.

What are mechanotransduction pathways in the context of ECM and cancer?

These are the roads cells use to feel and react to the ECM’s firmness. They include sensors like integrins and special channels. These paths are vital in cancer’s growth and spread, so stopping them could be an important step in fighting the disease.