Cancer-associated fibroblasts

Micke, P. and Ostman, A. (2004) Tumour-stroma interaction cancer-associated fibroblasts as novel, targets in anti-cancer therapy Lung Cancer 45 (Suppl. 2), S163-S175. 

Figure 7 Spheroid sprouting with cultured spheroids alone, in the presence of cancer-associated fibroblasts, or in the presence of normal tissue-associated fibrobiasts. Shortiy after polymerization of the reconstituted basement membrane, the device was imaged over 12 h. Cancer cells are GFP-expressing and fibroblasts were labeled with Cell Tracker Red. (A) Cancer cell spheroids alone did not exhibit sprouting. (B) Cancer cells sprouted into the surrounding matrix when cultured with CAFs. (C) When cultured with NAFs, cancer cells moved around the spheroid or within small clusters, but very little migration occurred outside of local movement. Originally published in Hockemeyer et al. (2014).

Just as in healthy tissues, tumors do not exist is isolation but are composed of an amalgamation of diverse cell types, including nonmalignant ones. In fact, cancer-associated fibroblasts (CAP), lymphocytes, endothelial cells, and macrophages together can routinely account for up to 90% of the tumor volume presumably stimulated by the cancer-associated inflammatory state and a vigorous but ineffective immune response. 

Ostman A, Augsten M. Cancer-associated fibroblasts and tumor growth— bystanders turning into key players. Curr Opin Genet Dev 2009 19 67-73. 

Olumi, A. F., Grossfeld, G. D., Hayward, S. W., Carroll, P. R., Usty, T. D., and Cunha, G. R. 1999. Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res. 59 5002-5011. 

Morales CP et al. Absence of cancer-associated changes in human fibroblasts immortalized with telomerase. Nat Genet 1999 21 115-118. 

Ko SY, Barengo N, Ladanyi A, Lee JS, Marini F, Lengyel E, Natna H. HOXA9 promotes ovarian cancer growth by stimulating cancta -associated fibroblasts. J Clin Invest 2012 122 3603-17. 

ET-1 also stimulates anti-apoptotic signal cascades in fibroblasts, vascular smooth muscles and endothelial cells (via phosphatidylinositol-3-kinase and Akt/pro-tein kinase B). In prostate and ovarian cancer, upregulation of endothelin synthesis and ETA receptors has been associated with a progression of the disease. The inhibiton of ETA receptors results in a reduced tumour growth. In malignant melanoma, ETB receptors are associated with tumour progression. Endothelins can also stimulate apoptosis in stretch-activated vessels via the ETB receptor, which contrasts the above-mentioned effects. The molecular basis for these differential anti- and pro-apoptotic reactions mediated by endothelins remains elusive. 

Beyond roles of chemokine receptors in hematopoiesis and innate immunity, roles for chemokines in adaptive immunity emerged. Moreover, other nonleukocyte migration properties of chemokine receptors have been identified. These include roles in the biology of endothelial cells (Chapter 15), cancer (Chapter 16), smooth muscle (Chapter 11), fibroblasts (Chapter 14), stem cells (Chapter 8), and all cell types associated with nervous system tissues (Chapter 17). In many instances, broad functional overlap is evident as chemokines can direct the migration of these cells just as they do with leukocytes. In certain instances, the ability of chemokines to retain cell populations within a specific microenvironment is as important as their migration-promoting properties. However, it is also clear that migration and retention are not the sole end points. 

There is no conclusive evidence from studies of cancers in dye workers that aniline is the causative agent. Two known metabolites of aniline induced sister chromatid exchange in the single study with cultured human fibroblasts. No studies on possible reproductive or developmental effects in humans associated with aniline exposures were located. 

Peterson, S. R., D. M. Gadbois, E. M. Bradbury, and P. M. Kraemer. 1995. Immortalization of human fibroblasts by SV40 large T antigen results in the reduction of cyclin D1 expression and subunit association with proliferating cell nuclear antigen and Wafl. Cancer Res 55(20) 4651-7. 

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