Quis custodiet ipsos custodies: who watches the watchmen?
Should this be said again? No cell is an island and in tissue-specificity and cancer, context is supreme. Decades ago, seminal recombination experiments illustrated the dominant role of mammary mesenchyme in directing epithelial development, and strongly suggested that the microenvironment plays a significant role also in the manifestation of carcinoma. More direct evidence for such functions came from a study demonstrating that an unadulterated microenvironment can suppress the malignant phenotype and re-direct tumor cells to give rise to normally functioning tissues and indeed healthy mice. One may wonder why such a stunning finding did not convince the scientific community to pay more attention to the role of context. The answers are complex, not the least of which is that concomitantly with this finding, the roles of oncogenes and mutations were being discovered. That excitement carried the day, specially because no one subsequently determined whether or not these mice generated from malignant cells contained tumorigenic mutations, and no new group reproduced the work. The following decade saw the discovery that even potent oncogenes could be ruled by context, and another couple of decades later it was shown that similar reprogramming of metastatic melanoma by an embryonic microenvironment was possible. There are many more examples which are not as clear cut, but are nevertheless compelling. The extensive literature of two-stage carcinogenesis, namely initiation and progression, indeed clearly indicates that 'initiation' and DNA damage alone are not sufficient to allow carcinogenesis. Implicit in these findings is: once a tumor or an oncogene, not always a tumor or an oncogene. A renewed focus on the tumor microenvironment as a therapeutic target has also led to the recognition that markers within the microenvironment could have predictive power. Two recently published reports identifying 'stromal signatures' in breast cancer patients prognostic for patient survival and predictive of response to chemotherapeutic treatment provide proof of this concept. In the current issue of The American Journal of Pathology, two independent studies identify a novel stromal marker, caveolin (Cav)-1, which predicts clinical outcome of breast cancer patients irrespective of its expression in tumor epithelium. Cav-1 is a scaffolding protein essential to the structure of caveolae, 'little caves' or invaginations in cellular plasma membranes. Cav-1 recruits and arranges lipids and proteins to these membrane sites to function in endocytosis and signal transduction. The observation that Cav-1 expression is attenuated in oncogenically transformed cells led to exploration of whether Cav-1 loss in mammary epithelium was causative. Although mechanistic data suggested that Cav-1 null mice exhibited aberrant epithelial growth, and that forcing Cav-1 expression in breast cancer cell lines inhibited growth and metastases in xenograft models, a clinical link proved elusive. However, MMTV-PyMT tumors transplanted into the fat pads of Cav-1 knockout mice displayed significantly enhanced growth (vs. wild-type mice), motivating investigation of whether stromal Cav-1 expression correlates with human breast cancer patient survival. This is precisely what Sloan et al. and Witkiewicz, Dasgupta, et al. demonstrate in this issue of AJP. Using tissue microarray data in conjunction with breast tumor sections and extensive patient survival data, Sloan et al. demonstrate that strong stromal Cav-1 expression is associated with smaller breast tumor size and grade, and is highly predictive of increased survival (Fig. 1). Patients with positive expression of stromal Cav-1 had a 91% ten year survival rate, vs. a 43% survival rate for patients lacking stromal Cav-1 expression. Importantly, there was no correlation between Cav-1 expression in the tumor epithelium and clinical outcome in either tissue arrays or tumor sections.
- Research Organization:
- Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
- Sponsoring Organization:
- Life Sciences Division
- DOE Contract Number:
- DE-AC02-05CH11231; R01CA064786; R01CA057621; U54CA126552; U54CA112970
- OSTI ID:
- 962951
- Report Number(s):
- LBNL-2073E; TRN: US200916%%454
- Journal Information:
- American Journal of Pathology, Journal Name: American Journal of Pathology
- Country of Publication:
- United States
- Language:
- English
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