Elkabets M, Gifford AM, Scheel C, Nilsson B, Reinhardt F, Bray MA, et al. Human tumors instigate granulin-expressing hematopoietic cells that promote malignancy by activating stromal fibroblasts in mice. J Clin Inv 2011;121:784–99.

We all know by now that cancers are not just masses of malignant cells but instead complex “rogue organs” with many different cell types that are attracted to, and corrupted by, the transformed cells. Some of the cell-attracting signals act locally, but recently attention has turned to endocrine signals sent by cancers that mobilize cells from the bone marrow. Elkabets and colleagues build upon initial descriptions of “instigator” tumors that can mobilize bone marrow cells into the circulation. Once mobilized, these bone marrow cells are also able to promote the growth of distant “responder” tumors that are usually indolent unless growing in a mouse that also has an instigator tumor. These bone marrow cells are able to promote tumor growth. The myofibroblast-rich reactive stroma that develop have now been identified as Sca+cKit hematopoietic progenitor cells, and the gene that was most upregulated in these cells was granulin. Granulin-positive bone marrow cells do not act directly to promote tumor growth but instead act on local fibroblasts in the tumor microenvironment to switch them to a cancer-promoting phenotype–and recombinant granulin alone has a similar effect on fibroblasts. Genes induced in fibroblasts by granulin include a range of chemokines, cytokines, and matrix remodeling factors already implicated in tumor promotion. In human breast cancer, high granulin expression has been correlated with the most aggressive triple-negative, basal-like tumor subtype and with reduced patient survival. These results may also help explain a number of clinical phenomena, for example the development of contralateral breast cancers and their association with poor survival, the simultaneous appearance of multiple metastases, and the fact that surgical resection of primary breast cancers in patients who present with distant metastases increases survival; thus, granulin and the Sca+cKit cells have potential as novel therapeutic targets.

Armstrong JL, Corazzari M, Martin S, Pagliarini V, Flasca L, Hill DS, et al. Onogenic BRAF signaling in melanoma impairs the therapeutic advantage of autophagy inhibition. Clin Cancer Res; Published OnlineFirst January 26, 2011; doi:10.1158/1078-0432.CCR-10-3003.

Metastatic melanoma is a very aggressive cancer with dismal survival rates that is in need of novel and innovative therapeutic strategies. In many studies, several antitumor drugs have effectively targeted autophagy, a lysosomal-mediated catabolic process, which can promote cell survival. In the present study, Armstrong and colleagues evaluated the in vitro and in vivo efficacy (using a subcutaneous xenograft model) of the estrogen receptor (ER) stress-inducing drugs fenretinide or bortezomib to induce autophagy and apoptosis in human melanoma-derived tumors harboring a wild-type or mutant BRAF gene and found that autophagy was significantly reduced in BRAF-mutant tumors. Rapamycin treatment was unable to stimulate LC3-II accumulation or redistribution in the presence of mutated BRAF, indicative of deregulated mTORC1-dependent autophagy. Knockdown of Beclin-1 or ATG7 sensitized BRAF wild-type cells to fenretinide- or bortezomib-induced cell death, demonstrating a prosurvival function of autophagy. In addition, autophagy was partially reactivated in BRAF mutated cells treated with the BH3 mimetic ABT737 in combination with fenretinide or bortezomib, suggesting autophagy resistance is partly mediated by abrogated Beclin-1 function. This intriguing discovery may lead to better therapeutic design for metastatic melanoma patients in clinical settings. In effect, inhibition of autophagy in combination with ER stress-inducing agents may provide a means of harnessing autophagy to derive therapeutic benefit in patients with BRAF wild-type melanoma.

Rolny C, Mazzone M, Tugues S, Laoui D, Johansson I, Coulon C, et al. HRG inhibits tumor growth and metastasis by inducing macrophage polarization and vessel normalization through downregulation of PlGF. Cancer Cell 2011;19:317–44.

Tumor-associated macrophages and abnormal blood vessels are hallmarks of malignancy. A recent article by Rolny and colleagues reveals a novel macrophage–vascular relationship and identifies a potential novel mechanism for exploiting the tumor microenvironment for targeted anticancer therapy. Histidine-rich glycoprotein (HRG) is a host-produced antiangiogenic and immunomodulatory factor that binds several tumorpromoting molecules and promotes phagocytosis. Its levels are decreased in human malignancies compared with their normal tissue counterparts, but the molecule has not been extensively studied in primary or metastatic disease—until now. Using a gain-of-function approach, Rolny and colleagues transfected HRG into 3 transplantable tumor cell lines. The resulting HRG+ tumors grew more slowly, and metastases were reduced. Blood vessels in HRG+ tumors normalized, as shown by tighter endothelial cell junctions, reduced hypoxia, improved perfusion, and increased activity of suboptimal doses of chemotherapy. But the effect of HRG in the tumor microenvironment was not limited to blood vessels. HRG also had direct effects on macrophages whose phenotype was skewed toward a classical activation pathway, associated with increased natural killer cells, dendritic cells, and cytotoxic CD8+ T cells, indicative of an immune-reprogramming event. However, if macrophages were depleted, the actions of HRG were abrogated. Importantly, HRG blocked macrophage production of the angiogenic factor placental growth factor (PlGF). It is fascinating to speculate that HRG could be a host response to malignancy, recognition of a malignant danger signal. At a time when we are learning that antiangiogenic approaches can sometimes be counterproductive as they aggravate hypoxia and encourage transformed cells to acquire a more malignant phenotype, this study suggests that “reeducation” of macrophages could be an antiangiogenic strategy and further supports a role for PlGF inhibition in cancer. However, the most important implication of this research may well be that reprogramming of just one cell type in the tumor microenvironment can have such profound effects on a host of other protumor cell types.

Cai H, Babic I, Wei X, Huang J, Witte ON. Invasive prostate carcinoma driven by c-Src and androgen receptor synergy. Cancer Res 2011;71:862–72.

Prostate cancer is the second leading cause of cancer-related deaths among men in the United States. Disease pathogenesis follows a defined progression from abnormal epithelial proliferation and prostatic intraepithelial neoplasia (PIN) to invasive carcinoma and, eventually, metastatic disease. Although early localized disease is usually curable, survival decreases with progression to invasive carcinoma and metastatic disease. In the case of advanced prostate cancer, castration-resistant prostate cancer often develops. Src (c-src) is a major regulator of many signal transduction pathways involved in growth control, cell migration, and maintenance of homeostasis. Although mutations of Src kinase have not been described in human prostate cancer, increased expression accompanying cancer progression has been reported. Cai and colleagues have investigated the effect of elevated c-Src expression coupled with enhanced expression of androgen receptor (AR), which results in a strong activation of Src kinase activity culminating in activation of the mitogenactivated kinase pathway and enhanced AR activity on prostate cancer development in vivo in mouse models. In these mice, the tubules progressed to frank carcinoma with invasion and displayed markers of epithelial-to-mesenchymal transition. These intriguing results suggest a potential role of nonmutated Src kinase in the genesis and progression of prostate cancer. Moreover, it is suggested that epigenetic changes that enhance the level of AR may select for increased expression of c-Src resulting in activation and promotion of malignant progression.

Zaidi MR, Davis S, Noonan FP, Graff-Cherry C, Hawley TS, Walker RL, et al. Interferon-γ links ultraviolet radiation to melanomagenesis in mice. Nature 2011;469:548–53.

Exposure to ultraviolet (UV) radiation is a known risk factor for malignant melanoma; however, in vivo studies linking UV damage to melanocyte biology are difficult to perform, owing mainly to the relative scarcity of melanocytes in normal skin. In a recent study, Zaidi and colleagues analyzed melanoma developing in mice carrying a genetically engineered susceptibility to melanoma due to melanocyte-directed expression of the hepatocyte growth factor and predisposed to melanoma in response to UVB irradiation. By incorporating a green fluorescent protein marker enabling isolation of melanocytes from mice after irradiation, Zaidi and colleagues showed an interferon-γ (IFN-γ) response signature. They subsequently demonstrated that 1) UVB-induced activation of the chemokine Ccr2, resulting in recruitment of IFN-secreting macrophages; 2) UVB-induced melanoma in these mice could be inhibited by blocking IFN-γ; and 3) IFN-γ-producing macrophages were common in human melanomas. These data link UV radiation and IFN-γ production to the pathogenesis of melanoma in both murine and human disease.