Tumor structure and extracellular matrix as a possible barrier for therapeutic approaches using immune cells or adenoviruses in colorectal cancer

Abstract

In this article we report about the role that tumor structure and extracellular matrix (ECM) may play in immunotherapy and in gene therapy using adenoviruses. We performed studies in a rat model for colorectal cancer, CC531, and in specimens of human colorectal cancer. The tumors were composed of two compartments, tumor cell nests surrounded by stromal cells. ECM proteins were expressed in the stromal part, where the blood vessels were also located. Furthermore, in several tumors, the tumor cell nests were surrounded by basal membrane-like structures. Therefore, in vascular approaches to treat cancer, therapeutic agents on their route to tumor cells may be hampered by ECM to reach tumor cells. We found that immune cells were abundantly present in tumors from colorectal origin. These cells were, however, not found in direct contact with tumor cells, but mainly in the stromal part of the tumor. Adenoviruses, when intravascularly injected, did not reach tumor cells in the CC531 rat model. Tumor cells were only infected, and even then in limited numbers, in cases of intratumoral injection. We hypothesize that ECM in a tumor is a barrier both for immune cells and for adenoviruses to make direct contact with these tumor cells, and thus limits colorectal tumor therapy.

Natural killer cells infiltrating human nonsmall‐cell lung cancer are enriched in CD56brightCD16− cells and display an impaired capability to kill tumor cells

“…[42][43][44] However, ultrastructural studies showed that NK cells display a marked ability to alter their shape, thus facilitating their extravasation and intratumor migration. 45,46 This would question the extracellular matrix proteins as a true physical barrier.…”

Conditionally Replicative Adenovirus with Tropism Expanded towards Integrins Inhibits Osteosarcoma Tumor Growth in Vitro and in Vivo

“…This can best be explained by inefficient dispersion of the CRAd through the tumor mass after intratumoral injection. Barriers within the established tumor, such as connective tissue and tumor matrix, may limit the spread of virus (34). In OS, osteoid calcification could be such a hurdle for viral therapy that needs to be overcome.…”

What's new in histochemistry and cell biology?

“…At early time points of adhesion and spreading of colon carcinoma cells in vitro, the epidermal growth factor through phosphorylation of focal adhesion kinase induced activation of 2 1 integrin and furthermore organization of the actin cytoskeleton involved in lamellipodia formation. In a rat model of colorectal cancer, evidence was obtained that the ECM may constitute a barrier for both immune cells and adenoviruses in tumor therapy (Kuppen et al 2001).…”