By Peter G. Traber, M.D. on October 29, 2015
Galectin proteins, particularly galectin-1 and galectin-3, are present in increased amounts in cancers of many types. In fact, expression of galectin-3 appears to be higher in the vast majority of solid tumors including skin, lung, breast, pancreas, ovarian, colon, thyroid and head and neck, among others.
Examining tumors for galectin-3 has gained some acceptance in clinical medicine. In thyroid cancers, for example, pathologists routinely stain tumor biopsies for galectin-3 to distinguish malignant from normal tissue, potentially reducing unnecessary thyroid surgeries. It has also been shown that the amount of galectin-3 expressed in some cancers correlates with the aggressiveness of the cancer and the ultimate prognosis of the patient, a finding that may be useful in clinical practice.
It’s not clear exactly why cancers express high levels of these proteins. Galectins are expressed in small amounts by normal cells, and it could be that these proteins simply react to inflammation and are therefore expressed at increased levels in cancers. Unfortunately, the increased presence of galectins serves a function that helps the cancer cells and hurts the patient.
In a sense, the cancer cells hijack the normal function of the protein. Galectin-3 is important for promoting cell-cell interaction and enabling cellular motility. A cell moving from one place to another in a culture dish is dependent on galectin-3, and cancer cells likewise make use of galectin-3 to move and grow.
Galectin-3 promotes the spread of cancer in three ways:
Invasiveness. One of the key characteristics of a cancer is that it invades surrounding tissue. Galectin proteins help cancer cells move, and therefore they promote the infiltration of the cancer cells into surrounding tissue.
Metastasis. Another characteristic of a cancer is that it can move from where it originated to other parts of the body. Colon cancer is a good model for the role of galectin-3 in metastasis. Colon cancer can progress from cancer in a polyp to an invasive cancer. The cancer penetrates the walls of the intestine and travels to the lymph nodes, then finally to the liver and other organs. If you look at the level of galectin-3 in each of those situations, the highest levels are in the metastases that are in the liver, and the lowest are in the cancer that’s in the polyp in the colon. This progressive increase in galectin-3 is one of the factors that leads colon cancer to metastasize in the liver.
Tumor growth. A tumor grows when more cancer cells live than die. Galectin-3 is observed to be involved in reducing cell death, thereby promoting the growth of tumors. Additionally, galectin-3 promotes the growth of blood vessels that bring blood supply to the tumor.
Galectins and the role of the immune system in cancer
Those three effects alone have led cancer researchers to believe that galectin-3 is an important target in treating cancer. However, galectin-3 also inhibits the patient’s immune system, thereby preventing immune cells from killing tumor cells. This immune effect of galectin-3 in cancer is particularly interesting because of the rising importance of cancer immunotherapy.
As background, blood cells circulate constantly through a tumor, just as they do through any other part of the body, and that includes white blood cells such as lymphocytes, or immune cells. Cancer cell genes are different from normal cell genes, so they should be recognized by the immune cells of the body as “non-self” and be attacked.
There is a theory of immune surveillance that holds that humans develop small cancers all the time throughout the course of their lives. According to this theory, the immune system recognizes these cancers as a threat while they are still small, kills them, and the cancer never progresses to become a larger tumor.
Regardless, cancer cells develop the ability to mask themselves from the immune system. When immune cells come in the vicinity of such a cancer cell, they don’t recognize it as non-self and don’t mount the response to kill it. That happens because the tumor cells secrete various substances that alter the micro-environment so that they’re not recognized. It’s kind of a cloaking device, if you will, for the cancer cells. There’s a broad spectrum of compounds that cancer cells can secrete to do this, and one of them is galectin-3.
Galectin-3 inhibits the immune system in two ways. First, galectin-3 inhibits what is called the afferent arm of the immune system, meaning it prevents the body from increasing the number of T cells it might normally mount in response to the tumor.
It also inhibits the efferent arm, which is the arm of the immune system that attacks the tumors. Normally, cytotoxic T cells — so called CD8 T cells — will recognize the tumor and secrete toxins called cytokines in its vicinity, which will then kill the tumor cells. Galectin-3 binds to the outside of the CD8 T cells and renders them anergic, meaning that even though they may recognize the tumor cell, they are unable to respond and secrete the toxins needed to kill the tumor.
All this suggests that the inhibition of the function of galectin-3 might be a possible target in restoring the immune system’s ability to attack cancer, and the basic science bears this out. Collaborators of ours at the Providence Cancer Center have shown that our lead galectin inhibitor GR-MD-02 is capable of enhancing the afferent arm of immune cell activation which improved tumor immunotherapy efficacy in mouse cancer models. Other collaborations of ours at the Ludwig Institute have published papers where they’ve taken our compounds and treated CD8 T cells in mixture with tumor cells and shown that, by inhibiting galectin-3, the ability of those T cells to kill tumor cells can be restored (1-4).
There is a vast amount of research being done by using a patient’s own immune system to treat cancer, and cancer immunotherapy is fast becoming the standard of care for many cancers. In my next CEO Perspective post, I plan to discuss the development of cancer immunotherapies and the potential role a galectin-3 inhibitor like GR-MD-02 might play in increasing their effectiveness.
These “CEO Perspectives” are a regular feature of our communication activities and may contain forward looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These statements relate to future events and use words such as “may,” “might,” “could,” “expect” and others. These statements include those regarding the hope that Galectin Therapeutic’ s development program for GR-MD-02 will show that it can effectively aid a person’s immune system to help fight cancerous tumors.. For a discussion of additional factors impacting Galectin’s business, see the Company’s Annual Report on Form 10-K for the year ended December 31, 2014, and subsequent filings with the SEC. You should not place undue reliance on forward-looking statements. Although subsequent events may cause its views to change, management disclaims any obligation to update forward-looking statements
Please look for future editions in which multiple aspects of our development programs for unmet medical needs will be addressed.
Reference List
- Demotte N, Bigirimana R, Wieers G, Stroobant V, Squifflet JL, Carrasco J, et al. A short treatment with galactomannan GM-CT-01 corrects the functions of freshly isolated human tumor-infiltrating lymphocytes. Clin Cancer Res 2014 Apr 1;20(7):1823-1833.
- Demotte N, Wieers G, Van Der Smissen P, Moser M, Schmidt C, Thielemans K, et al. A galectin-3 ligand corrects the impaired function of human CD4 and CD8 tumor-infiltrating lymphocytes and favors tumor rejection in mice. Cancer Res 2010 Oct 1;70(19):7476-7488.
- Demotte N, Stroobant V, Courtoy PJ, Van Der Smissen P, Colau D, Luescher IF, et al. Restoring the association of the T cell receptor with CD8 reverses anergy in human tumor-infiltrating lymphocytes. Immunity 2008 Mar;28(3):414-424.
- van der Bruggen P. [Is it possible to correct the anergy of T lymphocytes that infiltrate tumors?]. Bull Mem Acad R Med Belg 2009;164(5-6):183-191.
