Detecting and Monitoring Circulating Stromal Cells from Solid Tumors Using Blood-Based Biopsies in the Twenty-First Century: Have Circulating Stromal Cells Come of Age?

Abstract

Recent advancements in profiling genomic and proteomic aberrations of circulating tumor cells (CTCs) have provided a greater understanding of the underlying biology of tumor dissemination and subsequent metastases. Unfortunately, cancer is a complex disease with cancer growth, progression, and spread all intricately dependent not only on cancer cells, but also on a variety of nonmalignant cell types that make up the cancer environment. The concept of a “liquid biopsy,” which has recently gained great traction in the field of cancer research, revolves around analyzing the proteomic and genomic characteristics of CTCs and circulating tumor debris (i.e., circulating tumor DNA, tumor exosomes). However, a key concern of this single focus is the loss of vital information provided by nonmalignant cancer-associated cells, i.e., circulating stromal cells and circulating immune cells. Even though non-cancer immune cells are required contributors to the malignant behavior of tumors and are in many cases “abnormal” themselves, why is their study in “liquid biopsies” largely ignored? In this new era of targeted cancer therapies, i.e., immunotherapies, which target tumor cells and stromal cells, diagnostics for personalized treatment requires the ability to effectively account for both pro-cancerous nonmalignant cells and malignant cells. Given that blood harbors several circulating tumor-derived cells, representing a circulating metastatic niche, we must reevaluate what defines a “blood-based biopsy”(BBB) beyond conventional liquid biopsies to include circulating stromal cells as potential diagnostic targets.