Question

• Specify how vessels that are formed from angiogenesis in cancer are different from those formed during regular development or wound healing. How is this advantageous/disadvantageous to cancer progression?

Answer 1

The study of histological appearance of tumors and wounds produced a striking resemblance between several signaling processes involved in tumor progression similar to wound healing process. In this perspective, cancer cells forming carcinomas of breast, prostate, colon and lung release significant levels of PDGF (platelet derived growth factor). In wound healing process, the blood platelets aggregate to produce various factors including PDGF, transforming growth factor – ? (TGF – ?) and other vaso active factors.

Similarly PDGF is released by cancer cells or mesenchymal cells of stroma exhibiting the PDGF receptors. These cells include smooth muscle cells, fibroblasts and macrophages. Both these processes (wound healing and tumor progression) PDGF acts as an attractant and as mitogen in cancer cells and stromal cells. The PDGF is an important signal molecule in carcinoma cell and stimulate the proliferation of stromal cells (stromalization).

The tumor stroma produced by myofibroblast is different in its appearance from stroma of normal epithelial cells. The tumor stroma is known as desmoplastic stroma and contributes the hardness to the tumor mass. This stroma is formed by large amounts of collagen type I and III, fibronectin, proteoglycons and glycosaminoglycans.

The stromal fibroblasts support the tumor growth and carcinoma associated fibroblast (CAFs) are produced from carcinomas. The endothelial cells in a tumor are produced by proliferation of existing cells or by endothelial progenitor cells (EPCs) arriving through tumors stroma.

The stromal cells and carcinoma cells are therefore inter dependent and exchange various mitogenic and tropic factors. Angiogenec factors produced by morphogenic process include VEGF (vascular endothelial growth factor) play a major role in attraction of blood vessels. TGF – ?, fibroblast growth factors, interleukin – 8 and various other endothelial cells construct the capillaries and large vessels within the tumor contributing to the tumor associated vasculature and reduce the dependency on tumor associated stromal support in tumor progression.

Tumor progression is associated with angiogenic switch which includes various stages like neovascularization. This is accomplished by recruitment of endothelial precursor cells (EPCs) originated in bone marrow and enter the tumors through circulation. The stroma derived factor – 1 (SDF1) produced by stromal myofibril blast helps in the recruitment of EPCs into tumor mass resulting in construction of tumor associated vasculature.