Preferential Attachment of Peritoneal Tumor Metastases to Omental Immune Aggregates and Possible Role of a Unique Vascular Microenvironment in Metastatic Survival and Growth

Abstract

Controlling metastases remains a critical problem in cancer biology. Within the peritoneal cavity, omental tissue is a common site for metastatic disease arising from intraperitoneal tumors; however, it is unknown why this tissue is so favorable for metastatic tumor growth. Using five different tumor cell lines in three different strains of mice, we found that the omentum was a major site of metastases growth for intraperitoneal tumors. Furthermore, initial attachment and subsequent growth were limited to specific sites within the omentum, consisting of organized aggregates of immune cells. These immune aggregates contained a complex network of capillaries exhibiting a high vascular density, which appear to contribute to the survival of metastatic cells. We found that the vasculature within these aggregates contained CD105؉ vessels and vascular sprouts, both indicators of active angiogenesis. A subset of mesothelial cells situated atop the immune aggregates was found to be hypoxic, and a similar proportion was observed to secrete vascular endothelial growth factor-A. These data provide a physiological mechanism by which metastatic tumor cells preferentially grow at sites rich in proangiogenic vessels, apparently stimulated by angiogenic factors produced by mesothelial cells. These sites provide metastatic cells with a microenvironment highly conducive to survival and subsequent growth.

Mechanisms of peritoneal dissemination in gastric cancer (Review)

“…These results indicate that CCL22/CCR4 may participate in this selective infiltration process (80). Furthermore, milky spots are rich in capillaries and the surrounding vascular density is high (81). CD105 + vessels and vascular sprouts have been also located within milky spots, indicating that angiogenesis is active (81).…”

“…Furthermore, milky spots are rich in capillaries and the surrounding vascular density is high (81). CD105 + vessels and vascular sprouts have been also located within milky spots, indicating that angiogenesis is active (81). Additionally, milky spots also serves as a hypoxic niche, which enhances the self-renewing capacity of gastric cancer stem/progenitor cells regulated by hypoxia-inducible factor-1α (HIF-1α) (82).…”

Angiogenic Activity of the Peritoneal Mesothelium: Implications for Peritoneal Dialysis

“…Indeed, immunochemical staining of peritoneal biopsies showed that VEGF expression was confined mainly to the mesothelial monolayer (Aroeira et al, 2005;Combet et al, 2000). The mesothelial origin of peritoneal VEGF was ultimately confirmed in an elegant study, during which various cell types were isolated from the peritoneal lavage and the omentum, and analysed by several techniques for the ability to generate VEGF (Gerber et al, 2006). It transpired that omental mesothelial cells were responsible for the majority of peritoneal VEGF produced.…”

Omental milky spots in screening gastric cancer stem cells

“…In particular, omental milky spots are composed of numerous macrophage and lymphocyte aggregation and are involved in the clearance of particles, bacteria and tumor cells from the peritoneal cavity [5][6][7][8][9][10][11]. Omental milky spot is a wellknown site of metastases of carcinomas of the ovaries, stomach and colon.…”