Tumor Self-Seeding by Circulating Cancer Cells

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Tumor Self-Seeding by Circulating Cancer Cells
Summary
Cancer cells that leave the primary tumor can seed metastases in distant organs, and it is thought that this is a unidirectional process. Here we show that circulating tumor cells (CTCs) can also colonize their tumors of origin, in a process that we call “tumor self-seeding.” Self-seeding of breast cancer, colon cancer, and melanoma tumors in mice is preferentially mediated by aggressive CTCs, including those with bone, lung, or brain-metastatic tropism. We find that the tumor-derived cytokines IL-6 and IL-8 act as CTC attractants whereas MMP1/collagenase-1 and the actin cytoskeleton component fascin-1 are mediators of CTC infiltration into mammary tumors. We show that self-seeding can accelerate tumor growth, angiogenesis, and stromal recruitment through seed-derived factors including the chemokine CXCL1. Tumor self-seeding could explain the relationships between anaplasia, tumor size, vascularity and prognosis, and local recurrence seeded by disseminated cells following ostensibly complete tumor excision.

https://www.sciencedirect.com/science/a ... 7409014378

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Last paragraph -


“The present evidence provides clues that could elucidate certain enigmas in clinical oncology. The long-established association of large primary tumor size with poor prognosis in many types of cancer, thought to reflect the ability of larger cancers to release more cells of metastatic potential, may in addition reflect the ability of such aggressive cells to self-seed, promoting local-regional growth, acting in turn as a locus of expansion of these cells and priming for distant metastases. Similarly, the association of anaplasia with poor prognosis may be because micro-anatomical disorganization is a consequence of—and hence a marker of—assertive self-seeding. The hypervascularity of many cancers—and the association of such hypervascularity with poor prognosis—may similarly be explained. Our observation that a mammary tumor can be seeded by CTCs derived from lung-metastatic nodules raises the possibility of reseeding after tumor excision as a potential cause of eventual local recurrence. Moreover, that the phenomenon of self-seeding is hereby linked to tumor-specific and circulating cell-specific factors may create opportunities for the development of targeted therapies for the attrition of residual neoplastic cells from the breast and other organs.”

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Discussion to follow on metastatic tendencies and how they may not be true of the current hypothesis ..in sarcomas .

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https://www.ncbi.nlm.nih.gov/pubmed/20878451 Distant metastases do not metastasize

Finally found some study about the subject. (might not be the same study I red earlier.) There might be some individual cases, where metastases from colorectal cancer to liver have metastased futher, but this is exception not the rule. Sorry for going of topic, but as practically every decision I ever made is based on the theory that metastases dont spread futher. I take this topic very personally.

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Interesting thought Jussi

I feel it’s as important to me ,as well .
In descions we as patients make at each and every turn, challenge in our individual treatment choices.

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Discussion

Distant metastases do not metastasize.

https://www.ncbi.nlm.nih.gov/pubmed/20878451

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Abstract
Distant metastases (MET) are for most solid cancers decisive life-threatening events. Data about MET-free survival and survival after MET show a strong dependency on the kind of cancer and the prognostic features. Nonetheless, within biological subgroups, the MET process is very homogenous. Therefore, the growth rate can be estimated from initiation of MET to MET diagnosis and to time of death. Based on the known volume doubling time of breast cancer, the time of the first possible dissemination can also be estimated. Important consequences of these MET-initiation estimates are the hypotheses that almost all MET are initiated before removal of the primary tumor and that MET do not metastasize in a clinically relevant magnitude. Although breast cancer data were primarily used to form these hypotheses, the discussed MET process can be generalized to all solid cancers. The impact of these hypotheses on diagnostic, curative and palliative treatment, aftercare, and especially on clinical research would be important.

PMID 20878451 [Indexed for MEDLINE]

“Impact of tumor volume doubling time on post-metastatic survival in bone or soft-tissue sarcoma patients treated with metastasectomy and/or radiofrequency ablation of the lung”

The following medical write up gives light to how we as ASPS patients are viewed by our docs , when first diagnosed . We are viewed and thrown into the group of sarcomas whose prognosis is very challenging and most times grime looking . :/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5293497/

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Jussi
Is this what you were saying ? Seeding of tumors from primary ?
Breast cancer can be genetic ,
Family history ..

Please know I’m so trying to unearth what the heck to look for in our needle in the hay stack , to make all our lives manageable and ultimately cureable ..
As you have done and contributed for all these years..and many others .

My thoughts and brain storming are not just for today but certainly yesterday . With descions we’ve made without planning as we are a rare group without much
information .
Looking at yesterday’s results can bring a promise of a brighter tomorrow ? The cure ?
Love to you today and always

The Pearson’s
And

[arojussi]

The main point I am trying to make is, that in most cases asps-patients should have primary tumor removed. If metastases could send more metastases then this wouldnt be worth it. As tumors grow faster after surgery, because of rebound effect and primary might limit metastases growth primary surgery can initially seem counterproductive. If primary and only primary is sending metastases them removing it might be good idea especially if all metastases are managable. These days research supports removal of primary tumor and all metastases if possible in all soft tissue sarcomas not just asps. In asps even tiny tumors can metastasize, so if few mm metastases could send more metastases, then it would be impossible for sarcoma-patients to achieve long term survival with surgeries, but if only primary can metastasize, then this is possible.

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Excellent points ,Jussi

Here’s a great explanation of metastatic cancer travel

“In metastasis, cancer cells break away from where they first formed (primary cancer), travel through the blood or lymph system, and form new tumors (metastatic tumors) in other parts of the body. The metastatic tumor is the same type of cancer as the primary tumor.”

https://www.cancer.gov/types/metastatic-cancer

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Current approaches for avoiding the limitations of circulating tumor cells detection methods—implications for diagnosis and treatment of patients with solid tumors


Eight million people die of cancer each year and 90% of deaths are caused by systemic disease. Circulating tumor cells (CTCs) contribute to the formation of metastases and thus are the subject of extensive research and an abiding interest to biotechnology and pharmaceutical companies. Recent technological advances have resulted in greatly improved CTC detection, enumeration, expansion, and culture methods. However, despite the fact that nearly 150 years have passed since the first detection and description of CTCs in human blood and enormous technological progress that has taken place in this field, especially within the last decade, few CTC detection methods have been approved for routine clinical use. This reflects the substantial methodological problems related to the nature of these cells, their heterogeneity, and diverse metastatic potential. Here, we provide an overview of CTC phenotypes, including the plasticity of CTCs and the relevance of inflammation and cell fusion phenomena for CTC biology. We also review the literature on CTC detection methodology–its recent improvements, clinical significance, and efforts of its clinical application in cancer patients management. At present, CTC detection remains a challenging diagnostic approach as a result of numerous current methodological limitations. This is especially problematic during the early stages of the disease due to the small numbers of CTCs released into the blood of cancer patients. Nonetheless, the rapid development of novel techniques of CTC detection and enumeration in peripheral blood is expected to expedite their implementation in the clinical setting. It is of utmost importance to understand the biology of CTCs and their distinct populations as a prerequisite for achieving this ultimate goal.


https://www.sciencedirect.com/science/a ... 4416303498

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Introduction
Eight million people die from cancer each year1 and it is predicted that 13.2 million patients will do so in 2030.2 90% of deaths are caused by systemic disease.1 Systemic cancer spread means the formation of metastases, that is, secondary tumors arising from cells originating from the primary tumor. Thus, metastatic cancer cells are the subject of numerous studies and are an abiding interest to pharmaceutical and biotechnology companies. These cells include circulating tumor cells (CTC) in the bloodstream and disseminated tumor cells in the bone marrow. CTC are easier to analyze on a regular basis than disseminated tumor cells which require bone marrow aspiration—an invasive and painful procedure for patients with solid tumors.3

The evolution of tumor cells proceeds via multiclonal expansion which causes the tumor to be composed of multiple cell subpopulations. As a result of the accumulation of up to 6 mutations,4, 5 some cells acquire the ability to metastasize. The metastasis process consists of several sequential steps: local invasion of the primary tumor cells, intravasation, extravasation, and the establishment of distant metastasis.6 A simplified scheme of the metastatic cascade is presented in Fig 1.


Download : Download high-res image (823KB)Download : Download full-size image
Fig 1. Metastatic circuitry diagram. The major causes of difficulties in detecting and analyzing disseminated and circulating tumor cells (CTCs) include: (1) intertumor cellular heterogeneity, cancer cell genetic heterogeneity, metastatic potential of a small fraction of cancer cells, cancer cell dormancy, and the cell fusion phenomenon; (2) inefficiency of the metastatic process, various modes of cell movement, and gain/loss of cell surface markers; (3) the rarity of CTCs, various sizes of CTCs, various survival potentials of CTCs, and gain/loss of cell surface markers; (4) various cell sizes and various potentials of cells to survive in metastatic niche; (5) different colonization potential of cells, microenvironmental regulation of metastasis and cancer cell dormancy; and (6) systemic regulation of metastatic process.

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The term “metastatic colonization” refers to the final biological events required for cancer cells to form a clinically relevant metastasis at a secondary cancer site(s).

Abstract

Metastasis is the main cause of death from cancer. To colonize distant organs, circulating cancer cells must overcome many obstacles through mechanisms that we are starting to understand. Infiltrating distant tissue, evading immune defences, adapting to supportive niches, surviving as latent tumour-initiating seeds, and eventually breaking out to replace the host tissue, are key steps for metastatic colonization. These obstacles make metastasis a highly inefficient process, but once metastases are established current treatments frequently fail to provide durable responses. A better understanding of the mechanistic determinants of metastatic colonization is needed to better prevent and treat metastatic cancer.

Keywords: Cancer, metastasis, organ specific metastasis, metastatic colonization

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5029466/

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Circulating tumor cells promote the metastatic colonization of disseminated carcinoma cells by inducing systemic inflammation


Abstract

Circulating tumor cells (CTCs) have been studied well in the prognosis for malignant diseases as liquid biopsy, but their contribution to tumor metastasis is not clearly defined. Here we report that CTCs could promote the metastatic colonization of disseminated carcinoma cells by inducing systemic inflammation and neutrophil recruitment to pre-metastatic organs. Depletion of neutrophils in vivo could effectively abrogate the promoting effect of CTCs on tumor cell metastasis. In the presence of CTCs, the pro-tumor function of neutrophils was augmented, whereas the antitumor function of neutrophils was suppressed. Mechanically, CTC-derived ligands for TLR2 and TLR4 (TLR2/4) induced the systemic inflammation, thus increasing the production of proinflammatory cytokines such as G-CSF and IL-6 that could induce the conversion of neutrophil function from tumor-suppressing to tumor-promoting. Moreover, CTCs induced the production of endogenous TLR2/4 ligands such as S100A8, S100A9, and SAA3, which may amplify the stimulating effect that induces the expression of proinflammatory cytokines. The promoting effect of CTCs on tumor cell metastasis could be abrogated by suppressing inflammatory response with IL-37, an anti-inflammatory cytokine, or blocking CTC-derived ligands for TLR2/4. Identification of the metastatic axis of CTCs/systemic inflammation/neutrophils may provide potential targets for preventing tumor cell metastasis.

Keywords: circulating tumor cells (CTCs), disseminated carcinoma cells, metastatic colonization, inflammation, neutrophils


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5438660/

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Abstract

Tumor cells leave the primary tumor and enter the circulation. Once there, they are called circulating tumor cells (CTCs). A fraction of CTCs are capable of entering distant sites and persisting as disseminated tumor cells (DTCs). An even smaller fraction of DTCs are capable of progressing toward metastases. It is known that the DTC microenvironment plays an important role in sustaining their survival, regulating their growth, and conferring resistance to therapy. But we still have much to learn about the nature of these rare cell populations to predict which will progress and what exactly should cause concern for future relapse. Although recent technological advances in our ability to detect and molecularly and functionally characterize CTCs and DTCs promise to unravel this ambiguity, the timing of dissemination and the precise source of CTCs and DTCs profiled will impact the conclusions that can be made from these endeavors. In this review, we discuss the biology of CTCs and DTCs; the technologies to detect, isolate, and profile these cells; and the exceptions we must apply to our understanding of what role these cells play in the metastatic process. We conclude that a greater effort to understand the unique biology of these cells in context will positively impact our ability to use these cells to predict outcome, monitor treatment efficacy, and reveal therapeutically relevant targets to deplete these populations and ultimately prevent metastasis.

Keywords: chemoresistance, circulating tumor cells, disseminated tumor cells, dormancy, metastatic microenvironment, perivascular niche