P13.02 The ambiguity of brain metastasis response to radiotherapy driven by cellular adhesion molecules.
Sarmiento Soto M., Larkin JR.
Abstract BACKGROUND: Brain metastases treatments are usually based on surgery and radiation therapies with poor patient survival. Cellular adhesion molecules (CAMs) are promiscuous proteins highly involved in tumour progression. Owing to their dual functionality in structure and signalling, CAMs have emerged as potential targets in the clinic. It has been shown that CAMs can modulate radiation response in different types of tumours, triggering either apoptosis or resistance. However, this complex behaviour has not been studied in brain metastasis. In recent years, we have demonstrated a role of several CAMs during brain metastasis progression. For example, disrupting interactions between circulating tumour cells and brain vasculature using antibodies against ALCAM (CD166) and VLA-4 (α4β1), resulted in a significant decrease in metastatic colonies. Similarly, after LFA-1 (αLβ2) knockdown in tumour cells, brain metastasis growth was greatly reduced. On this basis, the aim of the current study was to determine the effect of concomitant stereotactic brain radiotherapy (SARRP) and anti-CAM treatments in breast cancer brain metastasis in vivo models. Methods: MDA231Br human breast carcinoma cells were treated with shRNA against either LFA1 or ALCAM. Cells were intracerebrally injected (5.000 cells/0.5 µl PBS) into the left striatum of female SCID mice. At day 14 after tumour injection, animals received a single dose of 15Gy in the striatum. Animals were culled 21 days after injection and brains processed for tumour quantitation. Results and Discussion: As previously shown, animals injected with LFA1 K.D. cells showed a 70% reduction in tumour burden 21 days after tumour implantation compared to those injected with the parent MDA231Br cells. Moreover, when irradiation was added, a synergistic effect (85% decrease in tumour growth) was evident in LFA1 K.D. injected animals. This study is particularly interesting from a clinical perspective, since anti-LFA1 therapies are common in the clinic for transplant rejection, joint inflammation or psoriasis treatments. In contrast, although animals injected with ALCAM K.D. MDA231Br cells showed a similar reduction (~80%) in tumour burden 21 days after injection, following irradiation tumour burden was comparable to that seen with the parental MDA231Br cells. These data suggest a pivotal role for ALCAM in brain metastasis progression and radiation response. Unravelling LFA-1 and ALCAM pathways in brain metastasis progression may lead to the successful combination of current clinical anti-inflammatory and radiation therapies and increase patient life expectancy.