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Abstract
Galectin-3 (Gal-3) is an extracellular matrix glycan-binding protein with several immunosuppressive and pro-tumor functions. The role of Galectin-3 in cancer stem-like cells (CSCs) is poorly investigated. Here, we show that prostate CSCs also colonizing prostate-draining lymph nodes of transgenic adenocarcinoma of the mouse prostate (TRAMP) mice overexpress Gal-3. Gal-3 contributes to prostate CSC-mediated immune suppression because either Gal-3 silencing in CSCs, or co-culture of CSCs and T cells in the presence of the Gal-3 inhibitor N-Acetyl-D-lactosamine rescued T cell proliferation. N-Acetyl-D-lactosamine also rescued the proliferation of T cells in prostate-draining lymph nodes of TRAMP mice affected by prostate intraepithelial neoplasia. Additionally, Gal-3 impacted prostate CSC tumorigenic and metastatic potential in vivo, as Gal-3 silencing in prostate CSCs reduced both primary tumor growth and secondary invasion. Gal-3 was also found expressed in more differentiated prostate cancer cells, but with different intracellular distribution as compared to CSCs, which suggests different functions of Gal-3 in the two cell populations. In fact, the prevalent nuclear and cytoplasmic distribution of Gal-3 in prostate CSCs made them less susceptible to apoptosis, when compared to more differentiated prostate cancer cells, in which Gal-3 was predominantly intra-cytoplasmic. Finally, we found Gal-3 expressed in human and mouse prostate intraepithelial neoplasia lesions and in metastatic lymph nodes. All together, these findings identify Gal-3 as a key molecule and a potential therapeutic target already in the early phases of prostate cancer progression and metastasis.
Highlights
Cancer is a multifactorial disease in which genetic and environmental factors concomitantly and progressively lead to neoplastic transformation and tumor development [1]
Because Gal-3 is a key molecule involved in several aspects of tumor progression and metastasis [10], and our previous data suggested that TPIN-SCs over-express the Gal-3 transcript [29, 30], here we further investigated the expression of Gal-3 in TPIN-SCs, and asked if Gal-3 expressed by prostate cancer stem-like cells (CSCs) plays a relevant role in the neoplastic process
We have found that TPIN-SCs use the extracellular matrix protein Tenascin-C to dampen T cell activation [30, 46], a mechanism that might favor their metastatic propensity
Summary
Cancer is a multifactorial disease in which genetic and environmental factors concomitantly and progressively lead to neoplastic transformation and tumor development [1]. Cancer cells are not solitary entities, as they are embedded within the tumor microenvironment, which is composed of several players among which stromal cells [4], immune cells [5], and non-cellular components such as collagen fibers and glycosylated molecules, constituting the extracellular matrix [6, 7]. A constant crosstalk between cancer cells and the tumor microenvironment ensures tumor development and progression. Galectin-3 (Gal-3) is an extracellular matrix glycan-binding protein whose function spans several biological processes, including immune modulation, chemoattraction, cell adhesion, activation, differentiation, and apoptosis [8]. Gal-3 has been referred to as: “the guardian of the tumor microenvironment” [9]
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