New Technologies Session
The keynote presentation opening the scientific session of the 2018 Cancer Stem Cell Conference was given by Dr. John Condeelis from the Albert Einstein College of Medicine in New York. His presentation addressed two fundamental questions: to what extent does single-cell vs collective-cell migration contribute to carcinoma progression, and what is the nature of those migrating cells? First, he explained the technique for answering these questions. Using multiphoton imaging technology and permanent, indwelling windows, the internal organs of living animals can be observed directly over time. This allows for the direct observation of a developing organ or tumor. In practice, multiple, small tissue volumes are examined with intravital staining, and those volumes are then “assembled” to provide a complete three-dimensional image of the tissue at a 0.4 micron resolution. This tissue construct allows you to see specific structures – eg, small blood vessels, cell types – and to zoom in on and see specific interactions, such as how a tumor cell actually enters a blood vessel.
Observing tumor cell migration
During the embryonic phase of organ development, it is primarily collective migration that is observed along with normal cell division. However, in the spread of invasive breast carcinoma, it is single tumor cells that migrate along collagen fibers toward blood vessels. There is no collective migration. The tumor cells pair with VEGF-rich macrophages as they move toward the blood vessel, and this pairing upregulates the invasive properties of the tumor cell. On reaching the vessel, tumor cells expressing the Mena invasive gene alter their cell membrane to create an invadopod that penetrates the vessel wall. This weakened point in the vessel, known as the tumor microenvironment of metastasis (TMEM), is critical, as is the actual site at which other tumor cells enter the vessel and are carried to distant sites. Thus tumor cells arrive individually and “pile up” at the TMEM until, one-by-one, they can pass through into the systemic circulation. Entrance of tumor cells into blood vessels occurs only at TMEM; this is a general feature of invasive carcinomas and is not limited to breast cancer. TMEM count is a clinically validated prognostic for distant metastatic recurrence in breast cancer patients.
Identifying the cells that seed the metastases
The specific cell type responsible for metastases was identified using an artificial blood vessel in a microfluidic device containing a medium rich in the signaling molecules secreted by normal blood vessels. The composition of signaling molecules was varied to see which tumor cells would enter the device. The tumor cells that responded to these signaling factors were captured and their expression profiles characterized. They were determined to be embryonic stem-like cells, but, as Dr. Condeelis noted, “…the only catch is they are cancer cells.”
Continued observation of the mouse lung through the indwelling window showed that spontaneous metastasis, ie, where the cells arrive via the TMEM doorway, is extraordinarily efficient. Ordinarily those cells can be hard to find because they are not dividing, but through the window and with high-resolution techniques the lungs were found to be absolutely filled with tumor cells. After exiting the blood vessel, these tumor stem cells were observed to associate with a locally derived macrophage and to assemble a new TMEM at this site distant from the primary tumor. The clinical significance of this is that if you could therapeutically block the TMEM, then you could target both the primary tumor and all metastases. One such agent, rebastinib in combination with a cytotoxic agent, is currently in clinical trials.
Other presenters in the New Technologies Session provided insights into ovarian cancer and glioblastoma biology and some potential therapeutic implications. Overviews were presented on the role miRNA-181a in ovarian cancer progression and how different tumor-cell spheroid models can provide insights into the nature of cancer stem cells. An analysis of brain tumor cells showed that myeloid-derived suppressor cells are increased in glioblastoma, that this is associated with a poor prognosis, and that these cells might be a potential therapeutic target. The relationship between macrophage iron binding capacity and phenotype was discussed in the context of exposure to glioblastoma exosomes.
Development and Genetics Session
This session consisted of presentations on a diverse range of cell type and cell signaling studies. The androgen receptor, a master regulator for prostate development and tumorigenesis, was found to modulate specific progenitor properties of luminal cells, including their ability to serve as a cell of origin for prostate cancer.
Oligodendrocyte precursor cells (NG2-positive OPC) are the cells of origin of astrocytomas and oligodendrocytomas. High endocytic recycling rates of these cells are linked with defective differentiation and associated with an increase in glioma formation.
A key feature differentiating invasive from noninvasive bladder cancer is that Hedgehog expression is lost in the invasive but retained in the noninvasive tumors. In vitro studies of cell lines derived from head and neck cancers showed that cells from HPV-positive tumors were more sensitive to cisplatin and had cancer stem cells compared with cell lines derived from HPV-negative tumors.