Cure Alveolar Soft Part Sarcoma International (iCureASPS)

When dormancy fuels tumour relapse


Abstract
Tumour recurrence is a serious impediment to cancer treatment, but the mechanisms involved are poorly understood. The most frequently used anti-tumour therapies—chemotherapy and radiotherapy—target highly proliferative cancer cells. However non- or slow-proliferative dormant cancer cells can persist after treatment, eventually causing tumour relapse. Whereas the reversible growth arrest mechanism allows quiescent cells to re-enter the cell cycle, senescent cells are largely thought to be irreversibly arrested, and may instead contribute to tumour growth and relapse through paracrine signalling mechanisms. Thus, due to the differences in their growth arrest mechanism, metabolic features, plasticity and adaptation to their respective tumour microenvironment, dormant-senescent and -quiescent cancer cells could have different but complementary roles in fuelling tumour growth. In this review article, we discuss the implication of dormant cancer cells in tumour relapse and the need to understand how quiescent and senescent cells, respectively, may play a part in this process.

https://www.nature.com/articles/s42003-021-02257-0

Introduction
Despite our growing knowledge of tumour biology and genetics, cancer remains a deadly disease. A high percentage of treated patients relapse after surgery or adjuvant therapies, and the tumour cells involved in the relapse often exhibit increased tumour propagating potential, manifested as local or distant disease recurrence. However, the mechanisms of tumour recurrence are largely unknown.

In addition to their genetic modifications, tumours comprise heterogeneous masses of cells that may differ in their capacity to support tumour growth, metastasis or resistance to therapy1. A growing tumour mass may consist of millions of proliferating cells, but also of some non- or slow-proliferative cells that are not sensitive to anti-proliferative therapies. Resistant dormant cells could fuel tumour regrowth after disease remission. However, our knowledge of the biology of dormant tumour cells is cripplingly limited. The recent identification of therapy-resistant cell populations with dormancy potential in both solid and hematologic tumours, including melanoma2, glioblastoma3, leukaemia4 and pancreatic5,6 and ovarian7 cancers suggests that these dormant populations, resistant to cancer treatments, play a role in tumour relapse. Furthermore, dormant quiescent cancer cells, also referred as slow-proliferating or slow-cycling cancer cells throughout this review—which stall in G0 phase or rarely enter the cell cycle, and/or senescent cancer cells in tumours could contribute to therapy resistance and tumour recurrence (Fig. 1)2,8. However, solid in vivo evidence of persistent tumour cells involved in tumour relapse are lacking and the molecular mechanisms behind such recurrence are largely unknown. Development of new genetic mouse models to track dormant cells would help to better understand how dormancy could fuel tumour relapse.

We know very well in ASPS that disseminated sarcoma cells can stay dormant for a long time. Single or small clusters of cells would stay attached somewhere without any growth, to small to be detected, and then start to grow by some reason. Sometimes years or decades after the primary tumor was resected.It is even typical for ASPS to have the first, usually lung metastases, appear in a year or two after the primary resection. More research is needed re. what can be done with the dormant cells to prevent them from proliferating and from forming new metastases.

Hi Olga
I’m doing a search on the forum on “dormancy” and coming up with a general consensus, of macrophages being a big driver of dormant cell awakening ?
And it looks like the microglial to macrophage responds by way of the brain can be a rather big contributor to the mechanistic immune response ? It’s a chemical change of the macrophage that turns the immune response from eliminating response to a progression response ?

After brain metastasis are diagnosed , I wonder what percentage of ASPS patients are found to have limited dissemination of mets or more importantly wide spread disseminated spread ? Especially after brain procedures verses lung and or primary surgeries , dissemination comparisons?

Here’s an article I posted in 2017

Differential Reactions of Microglia to Brain Metastasis of Lung Cancer

https://cureasps.org/forum/viewtopic.php?f=2&t=1432

In my search of dormancy , I came I came across a post you’d made in response to Dr. F, on endogenous growth inhibitor.
That is what I understand to be what a person would expect for the healthy immune system to react.

Prior to immune therapy and the lack of understanding of brain mets , (then came extended life with the advent of ICIs)brain mets were seen as the ultimate end to an ASPS patients life . So very little effort was given save that patients life I’m afraid .😕

I could truly see this especially happening with ASPS, with its ability to grow in an hypoxic environment ?

Especially after ablations surgeries etc back to back with no rest and recovery .It seems to be one of the many reasons that inflammation and the recruitment of microglial initiation to macrophages communication happens , when it by chance turns from an elimination response to a progression by a slight chemical change /response in these micro and or macro mets mets ?

“

Macrophages can contribute to tumor growth and progression by promoting tumor cell proliferation and invasion, fostering tumor angiogenesis and suppressing antitumor immune cells. Attracted to oxygen-starved (hypoxic) and necrotic tumor cells they promote chronic inflammation.”

Deb, I am not able to meaningfully assess the information we have re. brain mets emergence/treatment response to the further emergence of the new mets. Usually it is said that brain metastases mean the advanced disease. I have a feeling that any untreated/bulky tumors were connected to the faster progression of the existing mets and to emergence of the new mets in distant sites though. It was noted in many ASPS related publications that survival ASPS patients with the brain metastases if treated is typically above that usual sarcoma or cancer patients with ASPS. In our collective experience we usually do not see the resistance from the drs to get an active treatment of the brain metastases/surgery or ablation etc as the survival of the ASPS patients is expected to be long and their QOL merits this intervention.
How to balance the aggressive treatment with the need to keep the inflammatory processes at the minimal level possible? It is hard to say. We have already noted in the past and it is a common knowledge of this group that there is usually an increased growth in the distant mets or emergence of the new tiny mets after the major surgeries in ASPS. On the other hand it is statistically proven that surgery is beneficial for ASPS survival. At least it was before of the ICI.
With ICI, both, patient and treating dr, has to be aware of the consequences the inflammatory processes could have on the response to treatment. Do you remember the phenomenon of the rapid progression that occurs in some ICI treated patients? These cases are not frequent but happen. There was a study to combine the ablation with the ICI and they realized that they can actually cause the faster progression if the additional invasive treatment is done at the certain time like 10-14 days after the ICI intake day. It shows the complexity of the immune system and its inflammatory responses that can be beneficial or otherwise. Perhaps as the understanding improves, the blood cells measuring the white cells components could better guide the interventions. When planning any interventions, the effort has to be done to try to avoid any excess damage to the body esp. to the skin.