Preoperative radiotherapy and extracellular matrix remodeling in rectal mucosa and tumour matrix metalloproteinases and plasminogen components

Abstract

BACKGROUND. Preoperative radiotherapy reduces recurrence but increases postoperative morbidity. The aim of this study was to explore the effect of radiotherapy in rectal mucosa and rectal tumour extracellular matrix (ECM) by studying enzymes and growth factors involved in ECM remodeling. MATERIALS AND METHODS. Twenty patients with short-term preoperative radiotherapy and 12 control patients without radiotherapy were studied. Biopsies from rectal mucosa and tumour were collected prior to radiotherapy and at surgery. Tissue MMP-1, -2, -9, TIMP-1, uPA, PAI-1, TGF-beta1 and calprotectin were determined by ELISA. Biopsies from irradiated and non-irradiated peritoneal areas were also analysed. RESULTS. Radiotherapy increased the tissue levels of MMP-2 and PAI-1 in both the rectal mucosa and tumours while calprotectin and uPA showed an increase only in the mucosa after irradiation. The increase of calprotectin was due to an influx of inflammatory cells as revealed by immunohistochemistry. Prior to irradiation, the tumour tissues had increased levels of MMP-1, -2, -9, total TGF-beta1, uPA, PAI-1 and calprotectin compared to mucosa, while TIMP-1 and the active TGF-beta1 fraction showed no statistical difference. CONCLUSIONS. This study indicates a radiation-induced effect on selected ECM remodeling proteases. This reaction may be responsible for early and late morbidity. Interference of this response might reduce these consequences.

Effects of radiation on the metastatic process

“…In line with this, radiotherapy of prostate cancer and rectal cancer can increase MMP activity in the tumor and the local microenvironment (Angenete et al, 2009 ; Hovdenak et al, 2002 ; Kumar et al, 2002 ; Kumar et al, 2000 ). As stated above, these MMPs play a crucial role in invasion (Brown & Murray, 2015 ) and are correlated with cancer stage, metastasis and survival (Cho et al, 2005 ; Trudel et al, 2010 ).…”

Vascular and extracellular matrix remodeling by physical approaches to improve drug delivery at the tumor site

“…Several in vitro studies have shown that radiotherapy increased MMPs activity and ECM proteolysis leading to an enhancement of tumour cells migration and angiogenesis. Many research groups have observed MMP-2 upregulation after different RT protocols and for various tumour types such as pancreatic [46], colon cancer (25 Gy in 5 fractions overs 5 days) [47,48], lung cancer [49], breast cancer [50]. It has been suggested that MMP-2 may contribute to tumour cells dissemination [47,51,52].…”

“…Moreover, the inhibition of MMP-2 enhances tumour radiosensitivity in murine lung cancer (2 × 5 Gy) [49] while that of MMP-14 in murine breast cancer (3 x 6 Gy) [53] even enhanced the response to RT via an increased tumour perfusion. Some studies on rectal cancers showed an increase of MMP-1, MMP-3, MMP-9 mRNA concentrations after RT [47,54,55] and of PAI-I protein involved in radiation induced fibrosis [54,48,56].…”

Colorectal Cancer Cells Adhere to Traumatized Peritoneal Tissue in Clusters, An Experimental Study

“…Of a total of 331 patients, valid data were available for 272. Patients who received preoperative irradiation were excluded as irradiation affects MMP expression 137,138 .…”