Targeting Cancer and its
Microenvironment

By S. Vincent Rajkumar, M.D.

Over the last several years, it is increasingly apparent that effective therapy against cancer may require targeting both the cancer cell and its microenvironment. The role of the microenvironment in cancer cell progression involves several components including angiogenesis, evasion from immune surveillance, expression of adhesion molecules, interactions between cancer cells and stromal cells, and cytokine release. Several presentations at today’s Simultaneous Session Myeloma Microenvironment (8:00 a.m. – 10:00 a.m.) shed additional light on the critical role of the microenvironment in disease progression.

Dr. John Shaughnessy presents data using microarray analysis of more than 10,000 genes tested in patients with multiple myeloma. Only four significant genes distinguish patients with no lytic lesions from those with lytic lesions in multiple myeloma. These genes are DHFR, PSME, CKS2, and DKK1, all significantly over expressed in patients with bone lesions. DKK1 is an antagonist of the Wnt signaling pathway and thus blocks osteoblast differentiation and release of RANKL leading to inhibition of osteoclast activation and myeloma cell growth.

The role of angiogenesis is also being explored at this session. There is extensive data over the last several years that increased angiogenesis is a feature of disease progression across the spectrum of plasma cell disorders. Dr. Kewal Asosingh presents data to suggest the occurrence of an angiogenic switch that leads to increased VEGF expression by myeloma cells and subsequent aggressive tumor growth. The model is similar to that of carcinoma in situ progressing to aggressive malignancy following an angiogenic switch in solid tumors. The 5T2MM mouse model of myeloma was used in the experiments. In the pre-angiogenic stage the majority of myeloma cells were CD45+ and shifted to a CD45- phenotype with the angiogenic switch. The switch was accompanied by overexpression of VEGF by quantitative RT-PCR studies. Also, Dr. Yang Yang presents data on the role of soluble syndecan-1 (CD138) in promoting the growth and proliferation of myeloma cells. This effect appears to be partly due to enhanced angiogenesis.

Other abstracts in this session examine the role of osteoblasts, and myeloma cell osteoclast interactions in disease progression and development of bone lesions. Several abstracts also identify important new targets for novel therapy. Studies using agents that target the cancer cell and its microenvironment are being presented simultaneously at the Therapeutics for Plasma Cell Dyscrasias session today (8:00 a.m. – 10:00 a.m.).

Similarly, in the Simultaneous Session, CLL: Biology II (8:00 a.m. – 10:00 a.m.) abstracts examine the role of CLL cells and the microenvironment. Dr. Katja Mauerer and colleagues present data highlighting the role of cytotoxic T-cells in immune surveillance and discuss strategies to increase the ability of the cytotoxic T lymphocytes to kill primary CLL cells. Another abstract at this session presented by Dr. Ingo Ringshausen looks at the interaction between stromal cells and CLL cells. The data suggest that expression of p38 and MMP-9 are important for the enhanced survival of BCLL cells in contact with stromal cells.