Mr Hyde MUC1 Manipulates Tumor Microenvironment

Tumor-associated forms of MUC1 have been shown to be chemotactic for circulating immature human myeloid DCs [70]. This is mediated by the peptide epitopes in the tandem repeat region of the underglycosylated MUC1. Moreover, glycopeptides from the same region provide a maturation/activation signal for the DCs that migrate to the tumor site. These DCs that have matured under the influence of MUC1 produce IL-6 and TNF-a, cytokines that have been implicated in tumor metastasis and progression. They also fail to promote a type 1 response [70]. Hence, instead of promoting adaptive immunity for efficient immune surveillance, these DCs promote inflammation that mediates immunosuppression at the tumor site and later increased tumor invasion within the tumor microenvironment. A striking example of the "wrong" immune response that exists in this MUC1 modified tumor microenvironment is induction by the DCs at the tumor site of T cells that secrete IL-13 [70], a cytokine involved in suppression of tumor specific CTL and direct promotion of growth of tumor cells that bear IL-13 receptor [71].

As mentioned above, MUC1 has been linked to several signaling pathways via its cytoplasmic domain that has multiple phosphorylation sites and binding motifs for multiple kinases. In addition, it was reported recently that MUC1 regulates p53 transcription by binding to its regulatory domain [72]. P53 is a tumor suppressor gene whose function is often inactivated either through mutation or overexpression in a variety of cancers. Overexpression of MUC1 by tumor cells can lead to aberrant overexpression of p53. MUC1 expression also leads to decreased apoptosis of tumor cells under oxidative stress that occurs naturally during tumor expansion or in response to genotoxic agents [35]. This might be related to the ability of MUC1 to modulate transcription of the nuclear factor kB (NF-kB) as well as to regulate the ERK1/2 pathway and AP-1 mediated transcription [73]. The involvement of MUC1 in these networks reveals its key role in regulating tumorigenesis.

The impact of MUC1 on shaping the tumor microenvironment is well illustrated by a study in which MUC1 expression on tumor cells was suppressed by RNA interference. The siRNA treated pancreatic cancer cell line with low level of MUC1 expression showed a greatly reduced proliferative and metastatic capacity [74]. High levels of sialyl-Tn antigen, a carbohydrate structure decorating MUC1 on tumor cells, has been linked to increased tumor cell migration in vitro and decreased cell adhesion to the extracellular matrix molecules collagen type I, collagen type IV and fibronectin [75]. Moreover, MUC1 has been identified as a potential target in the colonization of metastasizing tumor cells by interacting with ICAM1 [31] or with E-selectin [76].

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