Circulating Cells with Macrophage-like Characteristics in Cancer: The Importance of Circulating Neoplastic-Immune Hybrid Cells in Cancer

Abstract

Cancer remains a significant cause of mortality in developed countries, due in part to difficulties in early detection, understanding disease biology, and assessing treatment response. If effectively harnessed, circulating biomarkers promise to fulfill these needs through non-invasive “liquid” biopsy. While tumors disseminate genetic material and cellular debris into circulation, identifying clinically relevant information from these analytes has proven difficult. In contrast, cell-based circulating biomarkers have multiple advantages, including a source for tumor DNA and protein, and as a cellular reflection of the evolving tumor. While circulating tumor cells (CTCs) have dominated the circulating cell biomarker field, their clinical utility beyond that of prognostication has remained elusive, due to their rarity. Recently, two novel populations of circulating tumor-immune hybrid cells in cancer have been characterized: cancer-associated macrophage-like cells (CAMLs) and circulating hybrid cells (CHCs). CAMLs are macrophage-like cells containing phagocytosed tumor material, while CHCs can result from cell fusion between cancer and immune cells and play a role in the metastatic cascade. Both are detected in higher numbers than CTCs in peripheral blood and demonstrate utility in prognostication and assessing treatment response. Additionally, both cell populations are heterogeneous in their genetic, transcriptomic, and proteomic signatures, and thus have the potential to inform on heterogeneity within tumors. Herein, we review the advances in this exciting field.

Tumor-associated macrophages: Prognostic and therapeutic targets for cancer in humans and dogs

“…One veterinary study found that of 39 complete blood counts from dogs with circulating macrophage-like cells, 46% had a diagnosis of cancer (including both histiocytic and non-histiocytic origin) ( 184 ). These cells have the potential to be detectable in higher numbers than circulating tumor cells as sources of phagocytized tumor DNA ( 185 ).…”

Adopted neoplastic cells and the consequences of their existence

“…Whether solitary adopted cells also proliferate is unclear because migratory cells can wander away from each other instead of forming a cluster. That at least some of the adopted cells are migratory, perhaps because they retain some features of their normal precursors, follows from their presence among circulating tumor cells [30,51,52], an observation that also implies that adopted cells can retain their neoplastic phenotype for some time after leaving the tumor.…”

“…Circulating tumor cells (CTC), discovered a century and a half ago [74], are neoplastic cells present in the blood of patients with solid tumors and are thought to include the precursors of metastases [75]. Paradoxically, a fraction or, in some cases, most of CTC released by some non-hematological tumors, such as melanoma, breast, ovarian, and pancreatic cancers, were found to carry CD45, a protein whose expression is normally restricted to bone-marrow derived cells [30,51,[76][77][78]. Hence, these cells (CTC-CD45) were viewed as a persistent artifact until an appeal to give them a closer look [77] revealed that they indeed exist [79] and that their concentration inversely correlates with the survival of patients with pancreatic cancer [30,51].…”

“…This hypothesis had laid fallow for six decades, until a serendipitous discovery revealed that human cancers grafted into laboratory animals can become metastatic and evade the immune response by forming hybrids with the cells of the host [25,26]. Since then, the ability of cell fusion to enable metastases in a variety of animal systems has been confirmed by many studies (reviewed in: [27][28][29][30]) and complemented by findings that cell fusion can also produce dormant tumor cells, change their drug sensitivity, suppress the ability to form tumors, which led to the concept of tumor suppressors [31], induce genomic and phenotypic instability [32], affect tumor cell evolution [33,34], change cell metabolism, produce circulating tumor cells, affect immune response, and, in synergy with oncogenes, produce invasive tumors that are similar to human cancers (reviewed in [27,29,[35][36][37][38][39][40][41][42]) Are these observations relevant to human cancers? This question prompted a search for cell hybrids in human tumors.…”

Root Bark Extract of Oroxylum indicum Vent. Inhibits Solid and Ascites Tumors and Prevents the Development of DMBA-Induced Skin Papilloma Formation

“…Cancer is characterized by the abnormal and uncontrolled proliferation of cells, which possess the ability to metastasize or invade other parts of the body [ 1 , 2 ]. The invading cells form a subset of neoplasms, which either form a tumor lump or a diffusely distributed cell population [ 3 , 4 ]. Chemotherapy is one of the common modalities of cancer treatment.…”