Extrinsic mechanisms - Tumor environment and drug resistance

The role of niche cells in supporting tumorigenesis and survival in cancer is now widely accepted, and key studies are prominent. For example, cancer-associated fibroblasts (CAFs) co-injected with tumor cells alter the niche cell state and stimulate angiogenesis and tumor invasion (Erez et al. 2010). Many niche cell communication signals promoting tumor survival and repair can likewise induce drug resistance in cancer cells. These include:

1) Cell communication molecules (e.g. growth factor receptors) that activate signaling pathways (MAP kinase, JAK/STAT, PI3-kinase/akt, NF-κB) can be directly altered to resist drug therapy (Sierra et al. 2010).

2) Chemokines (e.g. SDF-1, CCL2) can play a role in binding to G-receptors and are critical in recruiting tumor cells in close vicinity to the tumor environment.

3) Specific adhesion molecules are best exemplified by integrin α4β1 that binds VCAM1/ICAM1 and fibronectin and confers drug resistance in various tumors (Damiano et al. 1999).

In Multiple Myeloma little is known of the role or mechanisms by which specific niche cells protect MMCs from drug assault to potentiate resistance. Evidence to date centers on 3 main reports:

1. Tumor-associated macrophages (TAMs) mediate protection of MMCs from M (Zheng et al. 2009).

2. Components of BM stromal cells enhance NF-κB activity in MMCs and can enhance B resistance (Markovina et al. 2010).

3. Recent observations suggest that APRIL drives a subset of MMCs bearing a specific IgH-translocation into cell cycle (Quinn et al. 2011) and that this may underlie drug resistance.

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