Lung cancer is one of the leading causes of cancer-related death worldwide, accounting for approximately one-third of cancer-related deaths. The diagnosis of different lung cancers relies heavily on the use of IHC-based diagnostic tests and continued research into lung cancer biomarkers that can be used in IHC. Blood tests, including serum tumor marker tests, are increasingly used for early lung cancer diagnosis and can detect protein biomarkers with high specificity and sensitivity.

An increasing number of antibodies are available for detecting lung cancer-specific biomarkers used to determine different types of lung cancer and their cells of origin. Tumor marker tests measure serum levels of specific markers, and abnormal values above established upper limits can indicate lung cancer but may also result in false positives. These different cancer types include adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. Lung adenocarcinoma is a major subtype with unique molecular features, and identifying EGFR mutations is important for targeted therapy. Normal levels of certain markers can help rule out disease, while abnormal values may prompt further investigation.

Here, we look at some of the most common primary IHC markers for lung cancer and metastatic markers for lung cancer. Specific markers and other markers, such as those used for breast cancer, are also relevant in cancer diagnosis and can help distinguish between different cancer types. We also provide recommendations for specific biomarker antibodies for use in IHC. The role of tumor tissue and other cells in the tumor microenvironment, including healthy cells and other cells, can influence biomarker expression and cancer progression. Some markers, like NSE, are also elevated in neuroendocrine tumors and can help differentiate lung cancer from other conditions such as medullary thyroid cancer.

Aryl hydrocarbon receptor

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor known for sensing environmental toxins. It plays a regulatory role in tumor progression and immune signaling in lung cancer.

AhR is highly expressed in bronchial epithelial cells, affecting cell proliferation, differentiation, and cell-cell adhesion. It's key in diseases such as bronchitis and asthma, but it is also strongly implicated in the progression of lung cancer. It promotes cell proliferation, angiogenesis, inflammation, and apoptosis. AhR expression is also linked with smoking-related tumors as it may upregulate CYP1A1, releasing harmful factors into the lung tissue. It is, therefore, a marker of poor prognosis for lung cancer patients.

Studies suggest that reduced AhR expression may be linked to increased metastasis in non-small cell lung cancer, while its overexpression can influence inflammatory pathways such as IL-6 signaling. These findings highlight AhR’s potential as a biomarker for disease progression and therapeutic targeting. Ongoing research explores its function in cancer biology, particularly concerning environmental exposures and tumor microenvironment dynamics.

Figure 1. Western blot - Anti-Aryl hydrocarbon Receptor antibody [EPR7119(N)(2)] (ab190797).

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PD-L1

PD-L1 is a transmembrane protein that acts by inhibiting T cell activation and proliferation. PD-L1 protein detection by IHC testing is widely used as a predictive biomarker assay for anti-PD-1/PD-1/PD-L1 therapies for several cancer types, including lung cancer. Non-small cell lung cancer (NSCLC) accounts for 75% of all lung cancers, and approximately 50% of NSCLC cases will have the expression of PD-L1 in histology carried out on patient biopsies, making it a strong biomarker for this cancer type.

Figure 2. Immunohistochemistry (Formalin/PFA-fixed paraffin-embedded sections) - Anti-PD-L1 antibody [28-8] (ab205921).

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PD1

Programmed death-1 receptor is the receptor to the transmembrane ligand PD-L1 (above) and is found to be expressed on the surface of T-cells. Tumors use this PD-1/PD-L1 interaction to evade and suppress the immune response. These interactions are commonly seen in NSCLC as described above for PD-L1. Nivolumab, an anti-PD-1 drug, is approved for use in squamous NSCLC.

Figure 3. Multiplex immunohistochemistry - Anti-PD1 antibody [CAL20] (ab237728).

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Surfactant protein A

SPA is a large protein expressed within the lung's alveoli cells. It is responsible for fighting infectious diseases and reducing alveoli surface tension. SPA is also a biomarker used to detect adenocarcinoma in the lung. It is thought to be a marker of good prognosis as SPA is known to reduce tumor progression by recruiting natural killer cells to the tumor site.

Figure 4. Western blot - Anti-ALK antibody [SP144] (ab183332).

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SOX2

SOX2 is a transcription factor that plays a crucial role in the development of the embryonic lung. It is also important for the formation of the proximal airways, where it is used as a marker of proliferation and lung stem cells. It is also found to be overexpressed in over 80% of patients with lung squamous cell carcinoma (LSCC), a type of NSCLC. Therefore, it is commonly used as a marker of lung cancer cells derived from this squamous cell lineage.

Figure 5. Flow Cytometry (Intracellular) - Anti-SOX2 antibody [SP76] (ab93689).

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MET

The MET proto-oncogene is a transmembrane tyrosine kinase receptor. Its signaling cascade is involved in proliferation, apoptosis, and cellular migration. It also plays a role in the progression of NSCLC. Overexpression of MET in NSCLC leads to misregulation of proliferation and cell migration, leading to a more aggressive cancer.

Figure 6. Immunohistochemistry (Formalin/PFA-fixed paraffin-embedded sections) - Anti-Met (c-Met) antibody [EP1454Y] - N-terminal (ab51067).

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FAS

Fas, also known as CD95, is a cell surface receptor involved in programmed cell death. In lung cancer, Fas signaling has been linked to both apoptotic and non-apoptotic pathways, influencing tumor cell survival and immune evasion. Research shows that Fas can interact with NF-κB signaling, affecting how tumors respond to therapies targeting EGFR mutations. Additionally, alterations in Fas expression may contribute to resistance mechanisms and tumor progression. These findings support ongoing interest in Fas as a potential biomarker and therapeutic target in lung cancer, particularly in the context of immune modulation and treatment response.

Figure 7. Immunocytochemistry/ Immunofluorescence - Anti-Fas antibody [EPR5700] (ab133619).

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GSTP1

GSTP1 is an enzyme responsible for breaking down toxic compounds. In the lung, GSTP1 is highly expressed and is known to carry out the metabolism of carcinogens carried into the lung through smoking. Certain variants of GSTP1 are used as markers of lung cancer prognosis. The Ile105Val variant is associated with a reduced risk of lung cancer and a reduction in mortality from the disease.​

Figure 8. Immunohistochemistry (Formalin/PFA-fixed paraffin-embedded sections) - Anti-GST3 / GST pi antibody [EPR8263] (ab138491).

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Ki67

Ki67 is an essential protein involved in cell division and is commonly used as a marker of cellular proliferation. IHC staining for Ki-67 is a commonly used method for evaluating proliferative activity in various tumor types, including lung tumors. Studies suggest a key role of Ki-67 as a prognostic marker of NSCLC.

Figure 9. Immunocytochemistry/ Immunofluorescence - Anti-Ki67 antibody [SP6] (ab16667).

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MCM7

MCM7 is a chromosomal maintenance protein important during the cell cycle and has been associated with various cancer types, including lung cancers. Both MCM7 and Ki67 (the proliferation marker) are highly expressed in squamous cell carcinomas of the lung. Both are associated with a poor prognosis for the disease. MCM7 can also be used as an IHC biomarker from bronchial brushing.

Figure 10. Immunohistochemistry (Formalin/PFA-fixed paraffin-embedded sections) - Anti-MCM7/PRL antibody [EP1974Y] (ab52489).

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ASCL1

ASCL1 is a transcription factor necessary for neuroendocrine lung development and the growth of both SCLC and NSCLC. It acts as a marker of poor prognosis in NSCLC and looks promising as a potential druggable target for the treatment of NSCLC.

Figure 11. Immunohistochemistry (Formalin/PFA-fixed paraffin-embedded sections) - Anti-MASH1/Achaete-scute homolog 1 antibody [EPR19592] (ab213151).

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C-reactive protein

C-reactive protein (CRP) is a plasma protein produced by the liver in response to inflammation. In lung cancer, elevated CRP levels have been associated with systemic immune responses and may reflect tumor progression or treatment resistance. It is commonly seen in lung cancer patients who smoke. Smoking leads to chronic lung inflammation and the upregulation of several inflammation response genes, including CRP. Expression of CRP is a marker of lung squamous cell carcinomas and small-cell cancers but not adenocarcinoma of the lung.

Figure 12. Immunohistochemistry (Formalin/PFA-fixed paraffin-embedded sections) - Anti-C Reactive Protein antibody [Y284] (ab32412).

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MCM6

Minichromosome maintenance complex component 6 (MCM6) is a DNA helicase involved in the initiation of DNA replication. In lung cancer, MCM6 has been linked to increased cell proliferation and genomic instability. Mutations and altered expression of MCM6 may disrupt replication licensing, contributing to tumor development and progression. Recent studies have identified specific missense variants in MCM6 that could affect protein stability and function. These findings suggest that MCM6 may serve as a useful biomarker for lung cancer diagnosis and prognosis, particularly in understanding tumor behavior and identifying patients with aggressive disease profiles.

Figure 13. Immunohistochemistry (Formalin/PFA-fixed paraffin-embedded sections) - Anti-MCM6 antibody [EPR17686] (ab201683).

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References

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