Proteins and Lipids as Colorectal Cancer Biomarkers

Colorectal cancer, a prevalent and potentially life-threatening condition, demands a comprehensive understanding of its biomarkers. Cancer biomarkers may serve diagnostic, prognostic or other functions, and are important identifiers that enable better cancer diagnosis and treatment.

While many biomarkers are based on the genetic profile and detect the presence of genetic mutations to diagnose colorectal cancer, other molecular biomarkers have increasingly been tested and employed to help diagnose cancer and guide its treatment. Among these are protein and lipid biomarkers.

This article explores the pivotal role of proteins and lipids as biomarkers, and how they enable the diagnosis and prognosis of colorectal cancer.

Proteins are building blocks that the body requires to grow and function. Proteins are macromolecules made of amino acids, and the structure of each protein is encoded by different genes. As such, genetic mutations can sometimes result in deformed, misshapen and dysfunctional proteins, or an overexpression, i.e. an overproduction of protein.

Whether overproduced or dysfunctional, proteins play a crucial role in the onset and progression of colorectal cancer. The abnormalities in certain proteins can act as indicators and aid in early detection and prognosis.

What are some of the proteins that are currently used as colorectal cancer biomarkers, or have potential to be used as biomarkers?

Carcinoembryonic antigen (CEA)

CEA is a well-established protein biomarker for colorectal cancer. CEA is, more specifically, a glycoprotein that contains components of sugar molecules and amino acids. It is a naturally occurring protein, and is produced during fetal development. The protein production, however, stops right before the baby is born, and as such, it is normal for the initially-high CEA levels to drop with age.

CEA can still be found in low levels in healthy adults, but it doesn’t mean that a higher level immediately equates to a cancer diagnosis.

Elevated levels of CEA in blood is often a non-specific signal of disease. Higher levels of CEA have also been observed in patients with breast, lung, colorectal and pancreatic cancer patients, and as such, is not a biomarker that is unique to colorectal cancer patients. Its ubiquitous nature means that CEA levels are not typically used to diagnose cancer, and instead are used for disease prognosis.

CEA has been found to be overexpressed in more than 90% of colorectal cancer cases, and also increases in concentration in late-stage metastatic colorectal cancer. The level of CEA in a patient’s blood can be helpful in not only staging the cancer, but also determining a disease prognosis. CEA tests may also be conducted before and after treatment to check for cancer recurrence, or to see if a patient is responding well to treatment. High CEA levels would indicate that the treatment is not effective, or that cancer has recurred.

Tissue inhibitor of metalloproteinase-1 (TIMP-1)

Interaction between cells is done through cell receptors and the extracellular matrix, and cancerous growth can arise when these interactions do not function normally.

TIMP-1 is another glycoprotein that can be found in both cancerous and noncancerous tissue. TIMP-1 is one of four classes of TIMPs, proteins that inhibit the function of matrix metalloproteinases that are responsible for modifying the connections between cell receptors and the extracellular matrix.

In colorectal cancer, the synthesis of TIMP-1 is enhanced — its innate growth-promoting properties through apoptosis inhibition results in stimulation of tumor growth and the accumulation of cancer-related fibroblasts (CAFs) — a type of cell that makes up the connective tissue of the tumor microenvironment. TIMP-1 is also a significant indicator of cancer invasion, and studies have found that higher TIMP-1 levels are associated with a worse prognosis.

TIMP-1 has yet to be implemented clinically as a diagnostic and prognostic biomarker. Nonetheless, its role in colorectal tumorigenesis makes it a prospective novel biomarker for colorectal cancer.

Lipids is a broad term for organic compounds that include fatty acids, glycerides and other fatty compounds. You might recognize some of these examples of lipids: cholesterol, high-density lipoproteins (HDL) and low-density lipoproteins (LDL) — many of these are important indicators of one’s cardiovascular health. When it comes to colorectal cancer, changes in lipid metabolism are considered hallmarks of malignant progression and metastasis.

The study of lipids, or lipidomics, along with advancements in analytical tools such as mass spectrometry have helped identify a variety of lipids that have cancer diagnostic and prognostic potential. However, given that there are eight broad classes of lipids, of which there are over a million molecular species, narrowing down to specific lipids as biomarkers can prove challenging.

Analyzing lipid profiles

Instead of looking at specific lipids, one study analyzed the lipid profiles of colorectal cancer patients to determine if there was viability in diagnosing colorectal cancer. The team used an advanced mass spectrometry (MS) technique known as the MALDI-TOF MS technique, a highly sensitive and specific analytical test that has been applied into identifying a multitude of different cancers.

Of the 88 individuals whose profiles they analyzed, 40 were colorectal cancer patients, while 12 had colorectal polyps identified and the remaining 32 belonged in the control group. From their study, the team found that there were differences in lipid profiles between those with cancer and the control group, as well as between the cancer and polyp group. In addition, they also identified the polyketide lipid (810.1) as a potential differentiating biomarker — the lipid was present in the cancer group, but overexpressed in the polyp and control groups.

Another study analyzed the levels of selected lipid biomarkers together with other patient data, and utilized machine learning to determine the biomarker combinations that would best identify different colorectal cancer stages. These biomarker combinations were able to differentiate between stage 1-3 cancers, metastatic colorectal cancer with liver metastases (stage 4) and the control group. Analyzing the lipid profiles alongside the chemokine, gene and clinical data also allowed for better disease prognosis.

The link between lipids, obesity and colorectal cancer?

When tumors develop in colorectal cancer, they are linked to increased production of fats, a process called lipogenesis. This process involves creating new fats within the cancer cells, making their outer layer more resistant to damage and hard for treatments to enter. Saturated fatty acids (SFAs) in particular become plentiful due to increased fatty acid synthase (FASN) activity.

This whole process is influenced by a signaling pathway called mTOR kinase, which triggers the creation of proteins essential for cancer growth and spread. Scientists found that reducing the activity of FASN can slow down the invasion and spread of cancer cells.

Now, there's a theory suggesting that the rise of colorectal cancer in certain populations might be linked to changes in diet, especially favoring a Western-style diet rich in SFAs, which come from animal products. High consumption of these fats has been tied to obesity-related issues and insulin resistance. It can also activate toll-like receptors 2 and 4 (TLR2 and TLR4) related to inflammation, which is linked to cancer development.

These SFAs from the diet can also affect the levels of lipids in the blood. Substituting certain fats in the diet can lead to changes in cholesterol levels, but studies on whether this is directly tied to colorectal cancer have mixed results.

It's not just about what you eat, though. Changes in diet alone might not fully explain why cancer develops. For instance, a short-term diet change showed only a small link to specific genes, while increasing certain fats in the colon led to higher levels of inflammatory marker prostaglandin E2 (PGE2).

So, while a diet heavy in certain fats and obesity might be linked to a higher risk of colorectal cancer, it doesn't show a clear link to the overall risk of colorectal cancer when looking at blood lipid levels.

Proteins and lipids have much to offer as promising biomarkers in the realm of colorectal cancer. Whether utilized individually or as complements to existing clinical data, expanding the available cancer biomarkers can further improve diagnosing and prognosing colorectal cancer and better inform treatment regimens. As research progresses, a more nuanced understanding of these biomarkers will likely enhance our ability to combat colorectal cancer effectively.