Role of Pattern-Recognition Receptors (PRR)s in Cancer Progression
The Role of Pattern-Recognition Receptors (PRR)s in Cancer Progression
We aim to provide new insight into how PRR expression and signaling affects the progression of the cancers colorectal cancer (CRC) and multiple myeloma (MM). We found unexpected effects of PRR expression and signaling in MM and CRC. Our findings require further study, but appear to have implications for diagnosis and treatment of these cancers.
This project aims to provide new insight into how pattern recognition receptor (PRR) expression and signaling affects the progression of the cancer. PRRs expressed on immune cells recognize molecules associated with infection, stress or injury. Upon recognition of such factors, PRRs mount an inflammatory response which protects the host during the early phases of infection.PRRs can promote anti-tumor immune responses and are promising targets in cancer immunotherapy. PRRs may, however, play detrimental roles in tumorigenesis by mediating chronic inflammation when dysregulated. We are studying the two cancers; multiple myeloma (MM) and colorectal cancer (CRC), since previous results indicated that PRRs play important roles in the progression of these cancers. We have concentrated on assessing the role of the signaling PRRs; Toll-Like Receptors (TLR)s and Nod-Like Receptors (NLR)s. We are particularly interested in the role of TLRs 3,7 and 9 in cancer progression, since these are promising targets in cancer immunotherapy due to the potent type I IFN immune responses they induce. These TLRs recognize nucleic acids associated with viral infection, or released from injured cells, but can also be triggered by synthetic base-analogs. NLRs sense host molecules released during stress and cell-damage and trigger the inflammatory cytokine IL-1ß. Elevated levels of these cytokines are associated with poor prognosis in both CRC and MM. We have assessed the effect of TLR and NLR activators on CRC and MM cell lines and primary cells to determine the outcome of PRR stimulation on these cells. We have found that non-metastatic and metastatic intestinal epithelial cells (IEC)s respond differently to TLR stimulation. Metastatic IECs upregulate TLR3 and respond potently to TLR3 activators, in contrast to healthy and non-metastatic IECs. We have further found that activation of TLR3 induces an altered cytokine response characterized by potent chemokine production, but no type I IFN induction. TLR3 activation further promotes the invasive capacity of these cells. Our results indicate that altered TLR3 expression in cancerous IECs may in some cases promote the invasiveness of these cells, rather than promote anti-tumor immunity. We are currently revising a manuscript describing these findings. We further aim to verify these findings in patient samples. We have also assessed the effect of TLR and NLR activators on MM cell survival. Although stimulation with several PRR activators enhances survival of these cells, we have found that certain TLR7 and NLR activators impair the survival of these cells. This is surprising since TLR7 activators have previously been shown to promote MM survival. NLR activation also induces IL1ß production, which is known to enhance MM survival. We have also found that primary MM cells from patients display sensitivity to the same activators, while blood cells from healthy individuals tolerate these activators relatively well. Our data indicate that these activators induce apoptosis in MM cells rapidly. We are currently verifying these data, as well as investigating alternative mechanisms of cell death which are known to be induced by NLRs. We are currently assessing TLR7 and NLR expression in MM cells. We are also determining the signaling pathways which are activated in response to these ligands to determine why these cells are particularly sensitive to TLR7 and NLR activators, and whether this can be exploited in therapy.