Characterization of the Tumor Microenvironment and Tumor–Stroma Interaction by Non-invasive Preclinical Imaging

Abstract

Tumors are often characterized by hypoxia, vascular abnormalities, low extracellular pH, increased interstitial fluid pressure, altered choline-phospholipid metabolism, and aerobic glycolysis (Warburg effect). The impact of these tumor characteristics has been investigated extensively in the context of tumor development, progression, and treatment response, resulting in a number of non-invasive imaging biomarkers. More recent evidence suggests that cancer cells undergo metabolic reprograming, beyond aerobic glycolysis, in the course of tumor development and progression. The resulting altered metabolic content in tumors has the ability to affect cell signaling and block cellular differentiation. Additional emerging evidence reveals that the interaction between tumor and stroma cells can alter tumor metabolism (leading to metabolic reprograming) as well as tumor growth and vascular features. This review will summarize previous and current preclinical, non-invasive, multimodal imaging efforts to characterize the tumor microenvironment, including its stromal components and understand tumor–stroma interaction in cancer development, progression, and treatment response.

The dynamic tumor ecosystem: how cell turnover and trade-offs affect cancer evolution

“…Furthermore the edge of the tumor likely offers very different conditions in terms of substrates, normal cell architecture and exposure to the immune system (33,34). Hence, a number of agent-based models focus on tumor spatial heterogeneity in an environmental context, such as normal cells, stroma, and vasculature (4,5,35,36).…”

Frontiers in intravital multiphoton microscopy of cancer

“…Numerous microenvironmental cues can trigger transcriptional changes in cancer cells, which modulate their behavior (reviewed in Calvo and Sahai, Charras and Sahai, Fein and Egeblad, Conklin and Keely, Alexander et al, te Boekhorst et al, Bragado et al, and Ramamonjisoa and Ackerstaff). A recent IV‐MPM study used a fluorescent reporter for hypoxia in breast carcinoma cells to demonstrate that cancer cell invasiveness increases in hypoxia compared with normoxia .…”

“…Such studies have relied on simultaneous detection of one or two channels, commonly cancer cells and one host cell type or the extracellular matrix (ECM). Collectively, this work has revealed important information about cancer cell communication with stromal cells, such as fibroblasts, immune cells, including neutrophils, macrophages, and T-cells, as well as cancer cell interactions with collagen fibers in the ECM (reviewed in Calvo [2][3][4][5][6][7][8][9] ). However, to elucidate key mechanisms governing cancer progression and therapeutic efficacy, ideally all these interactions should be monitored simultaneously through three-dimensional (3D) space and over time in their native environment/or in living animals.…”

Missed Druggable Cancer Hallmark: Cancer–Stroma Symbiotic Crosstalk as Paradigm and Hypothesis for Cancer Therapy

“…The cancer microenvironment contributes to the evolution of cancer cells, thus increasing the complexity of cancer, a phenomenon that has been emphasized in recent reviews. [1,2] Dealing with this complexity requires finding certain universal principles that may reduce the diversity of tumors to a relatively small number of traits common to all of them. Such reduction was proposed by Hanahan and Weinberg in their well-known review "The Hallmarks of Cancer": "We foresee cancer research developing into a logical science, where the complexities of the disease.…”

“…The cancer microenvironment contributes to the evolution of cancer cells, thus increasing the complexity of cancer, a phenomenon that has been emphasized in recent reviews . Dealing with this complexity requires finding certain universal principles that may reduce the diversity of tumors to a relatively small number of traits common to all of them.…”