Immune Cells and Organ System
Cancer progresses as tumors grow and become immune cells and organ systems destroy the cancer. Cancer treatment seeks to stop or slow this progression by targeting cancer cells, immune cells, and organ systems. As we have learned in our work as cancer researchers, tumor cells are very dynamic and do not respond in a linear way to treatment. Instead, it appears that they can grow in various cycles where the state of the cancer cell is closely aligned with the state of the tissue in which it is growing. We call this tumor state a constant distribution state (CDS).
We discovered that the maturing cancer cells constantly change from a constant distribution state to a fixed state during their progression through the tissue, creating cycles where the cancer cell changes into a tumor cell. Each cycle takes three to four days. This observation, along with our earlier work showing that cells enter cycles of constant distribution on a smaller scale than those of cancer cells, led us to a new view of cancer cells. We believe that cells cycle into a fixed cancer cell state during their progression through a tissue. This tumor state is something we refer to as a cap.
Cancer Caps
Cancer caps can be patient-specific (for example, a cap based on tumor cells from a particular tumor type), organ-specific (for example, a cap that exists in a lung cancer patient or liver cancer patient), or tissue-specific (for example, a cap that exists in the lung or a liver cell line). Cancer appear when cancer cells change from a cap-like state to a tumor-cap state (with different patterns of cap formation depending on which tissue or organ the cancer cells are in).
Once the cancer cap becomes cancer cells. They continue to cycle back and forth between a cancer cap and their constant distribution state. During each cycle, cancer cells continue to behave as their cancer-cap state during the cap-to-tumor cycle. But they do not return to the cap-to-constant state during the cap-to-tumor cycle. Cells in our laboratory used cancer cap formation and cancer cap cycle cycling to identify cancer cells and cancer cells in mice that we called cancer cells that are dynamically preserved (DCSCs) (1). Cancer caps are clinically important, as they persist until the cancer ceases to progress and dies (2). In contrast, cancer cells that are not cancer caps do not maintain a constant distribution state, suggesting that cancer treatments targeting a constant distribution state are not optimal for patient-specific therapy.
Tumors Cancer
Ewing’s Sarcoma (EWS) and Peripheral Intratumoral Sarcoma (PIIS) are rare tumors that are unrelated to cancer. They do not present with typical tumors (for example, lung cancer) and are frequently found in bones and lungs. EWS and PIIS patients have similar outcomes: many patients die of cancer, but others are cured. The difference is that PIIS cells do not become cancer cells when they are removed from the body. In contrast, EWS cells cannot cycle back into a constant distribution state and remain in a cancer cap state. EWS patients show pathological features that are similar to DCSCs (for example, a fixed cancer cap) and PIIS cells (for example, a cancer cap that continuously changes). During our studies on EWS patients, we found that a series of four injections of immunomodulatory drugs to tumors. After surgery did not reduce DCSCs, and DCSCs persisted in PIIS patients after treatment.
We believe this results from the differential regulation of stem cell populations. With PIIS cells, we saw an overproduction of protein called TDP-43, which is a cancer stem cell marker (3). With EWS, we saw an overproduction of protein, SCLC, which we believe to be the same cell marker. We also saw an overproduction of caps within the bone cells that were removed during surgery. PIIS cells had caps within the bone cells, but the caps were small, and we found that DCSCs had larger caps. We hypothesize that DCSCs have more capacity for rapid tumor cell division and maintained their cancer caps. And decreasing the amount of protein TDP-43 and small caps in PIIS cells.
Laboratory DCSCs
In our laboratory, DCSCs have been shown to interact with immune cells. In a way that makes them less susceptible to apoptosis. As measured by the levels of protein that is released when cells are killed. We believe that DCSCs are more resistant to treatment, because of this interaction with immunologic pathways. Unlike the EWS and PIIS patient, DCSCs are patient-specific. We have tested DCSCs from both EWS and PIIS patients. And have seen that DCSCs that were derived from EWS patients do not have the cancer caps. Whereas DCSCs derived from PIIS patients do.
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