A review of its possible role in cancer treatment response and disease progression
This review summarizes the pathophysiological connection of galectin-3 and cancer presently in the literature, as well as the potential clinical value of galectin-3 as a prognostic oncology biomarker. Based on the preliminary data, the galectin-3 assay could become a contributing tool to help clinicians monitor treatment response and tumor progression, but further clinical studies evaluating galectin-3 levels and cancer progression are warranted.
Galectin-3 is a β-galactoside-binding protein expressed by a variety of different types of human cells. Galectin-3 is found in the nuclease, cytoplasm, and cell surface and is also secreted into the circulation. Galectin-3 as a biomarker has been confirmed with connections to inflammation, fibrosis, and overall risk of mortality in the general population. A blood serum test has been approved as a biomarker in high-risk cardiovascular patients to monitor potential heart failure. Elevated levels of galectin-3 in the serum have been linked to the development of several different cancers as well as cancer metastasis. Preclinical cancer models have shown galectin-3 to be associated with tumor cell transformation, invasive behavior, and metastasis. This review summarizes the pathophysiological connection of galectin-3 and cancer presently in the literature, as well as the potential clinical value of galectin-3 as a prognostic oncology biomarker. Based on the preliminary data, the galectin-3 assay could become a contributing tool to help clinicians monitor treatment response and tumor progression, but further clinical studies evaluating galectin-3 levels and cancer progression are warranted.
Galectins are a group of lectins characterized by a galactose-specific carbohydrate recognition domain (CRD) with affinity for beta-galactosides. Galectin-3 is a chimeric protein with an N-terminal domain necessary for homodimerization, a C-terminal domain with a single CRD, and a collagen-like sequence. It is a 31-kDa gene product found in the nuclease, cytoplasm, and cell surface and is also secreted into the circulation.1 The presently identified 15 galectin members are classified into 3 subgroups based on protein structure and the number of carbohydrate recognition domains within the polypeptide chain.2 Galectins characteristically mediate recognition of N acetyl galactosamine–containing glycoproteins on the cell surface and in the extracellular matrix. Galectin-3 is one of the most studied galectins, and increasing research is demonstrating that galectin-3 is directly and indirectly connected to cancer cell activity that can contribute to oncogenesis, angiogenesis, cancer progression, and metastasis.3-5
Galectin-3 influences oncogenesis and progression through a variety of pathways both inside6-12 and outside the cell.13-18 Elevated galectin-3 expression has been linked to several different malignancies, as well as neoplastic progression and therefore has the potential to be a useful biomarker in oncology.3-18
Presently, galectin-3 testing by enzyme-linked immune-sorbent assay (ELISA) has been approved by the US Food and Drug Administration (FDA) as a serum biomarker in chronic heart failure patients. A study that followed 592 patients who had been hospitalized for heart failure found that galectin-3 levels were correlated (P<0.002) with higher levels of inflammatory markers interleukin (IL)-6 and C-reactive protein.19 Approval of galectin-3 as a biomarker by the FDA in this population is based on the confirmed connection to inflammation, fibrosis, and risk of mortality.20 Galectin-3 levels have also been shown to be a reliable predictor of all-cause mortality in humans.21 The relationships between galectin-3 levels, demographic characteristics, and risk factors of cardiovascular disease—ie, smoking, high blood pressure, serum lipid, body mass index—were highlighted in the landmark Prevention of Renal and Vascular ENd-stage Disease (PREVEND) study, which looked at 7968 subjects with a median follow-up of approximately 10 years and found that galectin-3 levels were independently predictive of all-cause mortality and correlated significantly with the known risk factors for cardiovascular disease (P<0.0001).21
Galectin-3 has the potential to reflect changes in cancer status, as well as uncover other indicators of disease progression including inflammation, angiogenesis, and immunosuppression.
Correlation between galectin-3 and oncogenesis has become increasingly elucidated in the scientific literature over the past several years. As evidence becomes more compelling, approval of galectin-3 as an oncology biomarker is likely to follow the same path as it has for its use in cardiology. Future research is needed to demonstrate that galectin-3 can be used as a biomarker for other conditions as well. Preliminary research shows potential efficacy as a biomarker for systemic sclerosis, Alzheimer’s disease, and chronic kidney disease.22-24
Pathophysiology of Galectin-3 and Oncogenesis
While cancer initiation and progression is complex, all cancers share some common characteristics, including uncontrolled growth, disturbed adhesiveness, and resistance to apoptosis. Galectin-3 has been shown to influence many significant biological processes linked to cancer development and progression, including cell adhesion, proliferation, differentiation, mRNA splicing, cell-cycle progression, immune system evasion, inflammation, angiogenesis, and apoptosis.1
In vitro studies have shown that increased cellular galectin-3 expression directly correlates with apoptosis resistance in many cancers, including leukemia, breast cancer, and lymphoma.25-27 In addition to apoptosis resistance, malignant cells exhibit overexpression of galectin-3 that is shifted from localization in the nucleus to the cytoplasm. This overexpression and shift from nuclear to cytoplasmic localization is a predominant feature of many cancers including ovarian, breast, bladder, gastric, prostate, lung, pancreatic, and thyroid cancer as well as melanoma.2,28,29
Galectin expression is modulated during cell differentiation and can be influenced by physiological or pathological conditions; galectin-3 is specifically engaged in a multitude of complex pathways that are essential to cellular functions.30 All of the mechanisms by which galectins influence various cellular processes are not yet known; however, the interaction of galectins with numerous and significant intracellular proteins likely explains their influence on key cellular processes, including those involved in oncogenesis.30
The link between elevated galectin-3 and increased inflammation and fibrosis has been confirmed in the scientific literature.22,31-33 In addition to influencing inflammatory functions, galectin-3 can also modulate the immune response. An overexpression of galectin-3 has been shown to contribute to immunosuppression, specifically of T-cells, B lymphocytes, and suppression of IL-5 production.2,34 One pathway in which galectin-3 inhibits antitumor immunity is by clustering receptors on the cancer cell surface, thereby driving tumor-reactive regulatory T cell activation (which suppress killer T-cell and NK cell activity) and enhancing apoptosis resistance of cancerous cells, thus allowing the tumor to avoid immune destruction.35 It has been demonstrated that galectin-3 clustering has the potential to enhance galectin-3 binding affinity by as much as 10,000-fold.36
Another key physiological factor in tumor survival and progression is the process of angiogenesis. Both in vitro and in vivo studies have shown that galectin-3 stimulates angiogenesis.37 Additionally, a clustering of galectin-3 on the cancer cell surface leads to modulation of vascular endothelial growth factor, which further fuels angiogenesis and cancer progression.2
Utility as a Potential Monitoring Biomarker
Just as galectin-3 has been shown to help detect early heart disease, it can also be utilized similarly in oncology. Because studies have shown that galectin-3 is overexpressed in several cancers, it could prove to be a useful diagnostic biomarker.1
While more research is needed to clarify the physiological role for free galectin-3 circulating in the bloodstream of healthy individuals, research demonstrates that there is an increased concentration of galectin-3 circulating in the bloodstream of cancer patients. A 5-fold increase of galectin-3 in the sera of metastatic colorectal patients compared to healthy controls has been reported.38 Galectin-3 concentrations were also found to be significantly higher in patients with early stage and advanced cancers of the lung, head and neck, as well as melanoma.16,38,39 Galectin-3 monitoring in cases of thyroid cancer has been used because of the challenging nature of this cancer. In up to 15% of cases, diagnosis cannot be definitely determined by a fine needle aspiration biopsy with many patients receiving diagnostic surgery to remove a portion or the entire thyroid gland.40 In their review, Chiu and colleagues concluded that the galectin-3 biomarker “is a sensitive (78%), specific (93%), and accurate marker for the diagnosis of thyroid cancer.”41
The widespread utilization of galectin-3 blood assay for all cancers requires more studies focused on the sensitivity and specificity of testing; however, early indicators demonstrate clinical potential in this area of oncology.
Utility as a Potential Prognostic Biomarker
Current research indicates galectins can contribute to diverse physiological and pathological processes via a multitude of complex signaling pathways in the human body.42 To date, the most studied area of galectin-3 research in oncology involves evaluating treatment response and monitoring disease progression and risk of metastasis.37-41
Blocking the process of angiogenesis has become an effective therapeutic target in cancer treatment. Because elevated galectin-3 stimulates the angiogenic process, monitoring galectin-3 levels during treatment may be an effective prognostic strategy.37
Numerous in vitro and in vivo studies have shown that galectin-3 promotes neoplastic progression and metastatic activity via several different pathways.43-46 A variety of different cell lines have been utilized to demonstrate that when galectin-3 concentrations are increased, metastatic potential also increased significantly (P<0.05).47 More recently, it has been demonstrated that galectin-3 facilitated cell migration and invasion of melanoma in vitro and induced metastasis in vivo.48,49 Similar results were found utilizing pancreatic cells in which it was discovered that galectin-3 contributed to cancer progression.50
Research has demonstrated that relative to healthy individuals, galectin-3 levels were significantly elevated (P=0.014) in patients with malignancies of the breast, gastrointestinal tract, lung, and ovary, as well as melanoma and non-Hodgkin’s lymphoma.38 It has been shown that serum galectin-3 levels were moderately to highly elevated in men with metastatic prostate cancer compared to healthy controls (Pearson’s r=0.49, with 80% confidence interval of 0.14-0.71).51 Of note, when compared to prostate specific antigen (PSA) levels, galectin-3 consistently distinguished metastatic prostate cancer from cancer-free controls better than did PSA.51 Immunoblotting of prostate serum revealed uniformly increased levels of galectin-3 in metastatic prostate cancer patients, implicating galectin-3 as a potential complementary marker in the PSA blood test.51 The researchers conclude from the combined data that the application of galectin-3 as a biomarker in prostate cancer could improve treatment efficacy and contribute to more personalized treatment options by distinguishing prostate cancer subtypes.52 The studies also demonstrated that downregulation of galectin-3 resulted in increased apoptosis and decreased metastasis in prostate cancer cells.51
In addition to evaluating treatment response and monitoring disease progression, it will become clinically valuable to find ways to downregulate galectin-3 in cases of drug-resistant cancers and as a way to enhance chemotherapeutic agents. The literature suggests that downregulation of intracellular galectin-3 may be a useful strategy for improving chemotherapy treatment of some cancers.53 When galectin-3 is downregulated, the proapoptotic effects of chemotherapy agents, specifically cisplatin and etoposide, are positively influenced and help to enhance the efficacy of these drugs.54 There is potential to monitor the effectiveness of adjuvant drugs or new drugs using galectin-3 as a biomarker. More research is needed in this area.
Galectin-3 has the potential to reflect changes in cancer status, as well as uncover other indicators of disease progression including inflammation, angiogenesis, and immunosuppression. The scientific literature demonstrates that elevated serum galectin-3 levels are associated with a variety of cancer types. Overexpression of galectin-3 can be a contributing factor to disease progression and metastasis.43,47,49,50
We are beginning to see research addressing the potential role of galectin-3 monitoring as evidenced by a recent study that explored the use of galectin-3 testing as an adjunct to PSA testing in prostate cancer patients.51 A published case study illustrates the role galectin-3 tracking played in a case of stage IV ovarian cancer with underlying inflammatory comorbidities.55 In this case report, galectin-3 was used along with other markers to monitor inflammation and gauge cancer progression. Galectin-3 levels normalized as tumor control was achieved with chemotherapy. Clinicians must be aware that since galectin-3 is used as a biomarker of cardiovascular disease and is also linked with the inflammation process and associated morbidities that may cause elevated serum levels (as seen in the above case study), it can be challenging to associate it as a specific biomarker of cancer. This is true of other tumor markers that also lack the specificity as a cancer progression marker (eg, CA 125 is elevated in ovarian cancer, but also with any inflammatory condition in the pelvis). The use of other cancer markers in conjunction with galectin-3 plasma levels may be the best way to utilize this biomarker in cancer progression and treatment evaluation.
In addition, research indicates that finding ways to block galectin-3 expression and/or activity could have an impact on disease outcomes and may contribute to overall treatment success.56 The galectin-3 ELISA assay is presently readily available to clinicians. The preliminary data support the incorporation of galectin-3 testing as a biomarker of cancer progression and as an aid to prognosis determination.38,41,51,55 More research will help provide further clinical direction regarding the exact role galectin-3 can play as a biomarker in cancer diagnosis, treatment response, and disease progression, as well as modification of galectin-3 expression and activity as a treatment strategy in and of itself.
Conflict of Interest Disclosure
Isaac Eliaz, MD, MS, LAc, acknowledges his potential conflict of interest in that he is the owner of EcoNugenics, Inc, a dietary supplement company in Santa Rosa, California. Dwight McKee, MD, acknowledges no conflict of interest.