Highlights of This Issue

Abstract

Aggressive basal-like breast cancers (BBC) have characteristic interactions with their microenvironments, and these interactions may contribute to tumor progression. Stewart and colleagues used a coculture model to show that soluble factors secreted by BBCs caused increased macrophage differentiation, migration, and polarization to a population that expresses both M1 and M2 markers. These findings were mirrored in vivo, where dual-stained macrophages expressing both M1 and M2 markers were detected in basal-like microenvironments. Proteins secreted by BBCs were evaluated by cytokine protein arrays, and interleukin-1β was identified as a plausible target for modulating macrophage–cancer cell interactions in BBC.The morbicentric application of next-generation sequencing to various tumor types has unveiled a wealth of putative oncogenes and tumor suppressors. Before these data can be applied to drug discovery and development, functional characterization of somatic mutations is essential. Willard and colleagues report activating mutations in colorectal and gastric cancers in the G protein–coupled receptor CCK2R that increase receptor activity, activate multiple downstream signaling pathways, increase cell migration, and promote angiogenesis. The description of functionally activating mutations in CCK2R provides a novel and genetically validated druggable target to explore for the treatment of solid tumors.Signaling by insulin-like growth factors (IGF) and IGF-I receptor appears to be highly active in a variety of cancer types and has been shown to be required for tumor cell survival and tumor growth. Zumsteg and colleagues report that treatment of tumor-bearing transgenic mice with NVP-AEW541, a specific inhibitor of IGF-I receptor, fails to affect tumor cell survival. Rather, it delays progression to tumor malignancy. Upon IGF-I receptor blockade, sustained expression of IGF-II and of the IGF-II-binding form of insulin receptor (IR-A) in tumor cells suggests a compensatory role for IR-A during tumor growth and tumor progression.The K-Ras gene is mutated frequently in some human cancers, but rarely mutated in others. The mechanisms for tissue specificity of cancer mutations remain unclear. To address this question, Parikh and colleagues globally activated oncogenic K-Ras in adult mouse tissues. Whereas all examined tissues displayed robust Ras signaling, only a subset (oral, gastric, and lung epithelia) showed neoplastic progression within 6 weeks after K-Ras activation. These Ras-responsive tissues exhibited nuclear phospho–extracellular signal–regulated kinase1/2 (Erk 1/2), a key downstream effector of Ras signaling. In contrast, Ras-unresponsive tissues displayed only cytoplasmic phospho-Erk1/2. Thus, cytoplasmic retention of growth signaling molecules may represent a novel tumor suppressor mechanism for some cells.