I’d like to summarize some new and interesting data presented at the 101th annual meeting American Association of Cancer Research in Washington DC last week. The main message I’ve learned throughout the talks was that cancer cells that possess stem cell-like (aka cancer stem cells = CSC) properties should be blamed for all stages of metastatic processes.
We know that CSC are the more likely the population responsible for chemo-, radiation resistance and for relapses. Now we learn more about how CSC involved into tumor dissemination, niche hijacking, metastasis development and tumor dormancy.
Jeremy Rich noted that the ability to invade and metastasize proposed as a new functional characteristics of CSC. Danny Welch, giving overview of metastatic cascade in plenary session, highlighted that metastasis are 90% clonal, basically the product of a few or even one cell.
Joerg Huelsken reminded us that the final phases of the metastatic process are very inefficient. Only 1% of cancer cells from primary tumor can form micrometastasis and only 0.01% can make macrometastasis. What kind of cells are they? He showed that in breast cancer model only CD24+/CD90+ possessed CSC properties and can make metastases, but not other cells derived from primary tumor or single macrometastasis. Colonization and metastasis formation by CSC is highly niche-dependent. CSC expanded in colonization phase of metastatic process, but shrinks in number after macrometastasis was formed. He proposed that not all of CSC wil form metastasis, some of them after extravasation will go to dormancy.
Klaus Pantel highlighted that circulating tumor cells (CTC) use bone marrow as reservoir. He reported that they were able to establish cell lines from bone marrow-derived CTC in order to study their identity. More new data emerged indicating that CTC could be a “product of EMT“. He thinks that CTC can adapt to hypoxic conditions in bone marrow niches and possess “stemness”. Sure enough Lalit Patel presented a work where in xenotransplant model CD133+/CD44+ human prostate CSC were identify as a large fraction of disseminating cells in bone marrow. These data suggest that CTC can hijack bone marrow niches.
John Condeelis group developed tools that allow us to visualize and study initial steps of metastatic cascade – intravasation and systemic dissemination. Manipulating by known factors which promote intravasation (macrophages, extracellular matrix) and developing “artificial blood vessel”, his team collected disseminating cancer cells and studied them precisely. It turns out that these disseminating cells have the following properties: EMT (epithelial-mesenchymal transition) markers, dormant (quiescent), resistant to drugs and irradiation, upregulation of stem cell markers, upregulation of genes suppressed apoptosis and repair DNA damage. In other words these cells are CSC.
Ann Chambers indicated that there is a direct correlation between metastatic potential (phenotype) and CSC and dormant cancer cells. She noted that dormant mammary carcinoma cells are resistant to drugs and sustain tumorigeneity. Chemotherapy does not reduce number of dormant cancer cells and has no effect on their late-developed metastasis.
Robert Weinberg concluded that non-stem cells withing the primary tumor can undergo EMT and become metastatic CSC. So, EMT program allows cancer cell to 1. self-renew and 2. metastasize. This program is already done in CSC from primary tumor and does not required additional mutations in order to launch metastatic cascade.
Many posters presented data that indicated a strong link between EMT, CSC and metastatic program. Speakers and presenters did a significant amount of work to identify specific factors and signals which orchestrate CSC-driven metastatic cascade and can be used as therapeutic targets and prognostic markers. I’d skip this, because there were too many factors and markers presented and all of them should be published shortly. Stay tuned!
Overall, mounting evidence emerged from many laboratories around the world that CSC of primary tumor underlies all stages of metastatic process and can be responsible for tumor dormancy. While I was attending a conference, the first clinical case report came up, indicating that vascular emboli in lung metastatic site of breast cancer contain cells with “stemness” signature, independent of the original primary tumor.