Tumor Dormancy Research Articles

The rationale for treating uveal melanoma with adjuvant melatonin: a review of the literature

BackgroundUveal melanoma is a rare form of cancer with high mortality. The incidence of metastases is attributed to early seeding of micrometastases from the eye to distant organs, primarily the liver. Once these seeded clusters of dormant tumor cells grow into larger radiologically detectable macrometastases, median patient survival is about 1 year. Melatonin is an important hormone for synchronizing circadian rhythms. It is also involved in other aspects of human physiology and may offer therapeutic benefits for a variety of diseases including cancer.MethodsArticles involving the physiological effects of melatonin, pharmacokinetics, and previous use in cancer studies were acquired using a comprehensive literature search in the Medline (PubMed) and Web of Science databases. In total, 147 publications were selected and included in the review.ResultsMelatonin has been observed to suppress the growth of cancer cells, inhibit metastatic spread, enhance immune system functions, and act as an anti-inflammatory in both in vitro and in vivo models. Melatonin may also enhance the efficacy of cancer treatments such as immuno- and chemotherapy. Numerous studies have shown promising results for oral melatonin supplementation in patients with other forms of cancer including cutaneous malignant melanoma. Cell line and animal studies support a hypothesis in which similar benefits may exist for uveal melanoma.ConclusionsGiven its low cost, good safety profile, and limited side effects, there may be potential for the use of melatonin as an adjuvant oncostatic treatment. Future avenues of research could include clinical trials to evaluate the effect of melatonin in prevention of macrometastases of uveal melanoma.

Transcriptomics and Metabolomics Identify Drug Resistance of Dormant Cell in Colorectal Cancer.

Background: Tumor dormancy is an important way to develop drug resistance. This study aimed to identify the characteristics of colorectal cancer (CRC) cell dormancy. Methods: Based on the CRC cohorts, a total of 1,044 CRC patients were included in this study, and divided into a dormant subgroup and proliferous subgroup. Non-negative matrix factorization (NMF) was used to distinguish the dormant subgroup of CRC via transcriptome data of cancer tissues. Gene Set Enrichment Analysis (GSEA) was used to explore the characteristics of dormant CRC. The characteristics were verified in the cell model, which was used to predict key factors driving CRC dormancy. Potential treatments for CRC dormancy were also examined. Results: The dormant subgroup had a poor prognosis and was more likely to relapse. GSEA analysis showed two defining characteristics of the dormant subgroup, a difference in energy metabolism and synergistic effects of cancer-associated fibroblasts (CAFs), which were verified in a dormant cell model. Transcriptome and clinical data identified LMOD1, MAB21L2, and ASPN as important factors associated with cell dormancy and verified that erlotinib, and CB-839 were potential treatment options. Conclusion: Dormant CRC is associated with high glutamine metabolism and synergizes with CAFs in 5-FU resistance, and the key effectors are LMOD1, MAB21L2, and ASPN. Austocystin D, erlotinib, and CB-839 may be useful for dormant CRC.

Invivo partial cellular reprogramming enhances liver plasticity and regeneration.

Mammals have limited regenerative capacity, whereas some vertebrates, like fish and salamanders, are able to regenerate their organs efficiently. The regeneration in these species depends on cell dedifferentiation followed by proliferation. We generate a mouse model that enables the inducible expression of the four Yamanaka factors (Oct-3/4, Sox2, Klf4, and c-Myc, or 4F) specifically in hepatocytes. Transient invivo 4F expression induces partial reprogramming of adult hepatocytes to a progenitor state and concomitantly increases cell proliferation. This is indicated by reduced expression of differentiated hepatic-lineage markers, an increase in markers of proliferation and chromatin modifiers, global changes in DNA accessibility, and an acquisition of liver stem and progenitor cell markers. Functionally, short-term expression of 4F enhances liver regenerative capacity through topoisomerase2-mediated partial reprogramming. Our results reveal that liver-specific 4F expression invivo induces cellular plasticity and counteracts liver failure, suggesting that partial reprogramming may represent an avenue for enhancing tissue regeneration.

Considering therapy-induced senescence as a mechanism of tumour dormancy contributing to disease recurrence.

The capability of tumour cells to escape from therapy-induced senescence, as well as cell-non-autonomous functions of senescence, support the premise that senescence could serve as one pathway to tumour dormancy (among others that include quiescence and diapause) that is permissive for disease recurrence. Consequently, the pharmacologic targeting of senescent tumour cells could mitigate the risk for cancer resurgence, thereby enhancing the therapeutic efficacy of cancer chemotherapy.

Single-cell sequencing reveals MYC targeting gene MAD2L1 is associated with prostate cancer bone metastasis tumor dormancy

BackgroundAmong malignant tumors, bone metastasis is frequently associated with prostate cancer which is seen in about 80% of patients. During cancer treatments, some tumor cells switch to a "dormant mode" to help tumor cells avoid attack from the immune system and anti-tumor therapies. In this dormant mode, tumor cells can be resuscitated, causing cancer to reoccur. The generally accepted explanation for this phenomenon is that the tumor cells have spread to the bone marrow before treatment and are dormant in the bone marrow. However, the key mechanism for inducing and maintaining the dormancy of these prostate cancer disseminated tumor cells in the bone marrow is still unclear. Therefore, studying the dormancy mechanism of tumor cells in bone metastasis is of great significance for the treatment and the prevention of recurrence of prostate cancer.MethodsWe obtained single-cell RNA-seq data of tumors from mouse models of prostate cancer bone metastasis mouse model numbered (GSE147150) from the GEO database, and obtained RNA-seq expression data and clinical information from The Cancer Genome Atlas Program (TCGA) of prostate cancer patients from the USCS Xena database. Screening of differential genes and annotation of GO functions were performed separately. Subsequently, the screened differential genes were compared and analyzed with 50 classic Hallmark signaling pathways, and the prognosis analysis of prostate cancer patients in TCGA data was performed to discover the key genes of the dormant mechanism of tumor cells in bone metastasis, and obtain new biomarkers that can be used to predict the prognosis of patients.ResultsA total of 378 differentially expressed genes were screened, of which 293 were significantly up-regulated and 85 were significantly down-regulated. Among them, the up-regulated genes were mainly related to the immune response, and the down-regulated genes were mainly related to the cell cycle. Through GSVA (Gene set variation analysis), it is found that there are differences in a total of 3 signal pathways: COMPLEMENT, MYC_TARGETS_V1 and MYC_TARGETS_V2. By comparing and analyzing the significantly down-regulated genes in dormant tumor cells with MYC_TARGETS_V1, MYC_TARGETS_V2, three significantly down-regulated genes were obtained: Ccna2, Mad2L1 and Plk1.ConclusionIn summary, our findings indicate that the MYC targeting gene Mad2L1 is potentially related to the dormancy mechanism of prostate cancer. At the same time, Mad2L1, a gene associated with dormant prostate cancer cells, may be used as a biomarker for prognostic survival.

The nerve-tumour regulatory axis GDNF-GFRA1 promotes tumour dormancy, imatinib resistance and local recurrence of gastrointestinal stromal tumours by achieving autophagic flux

Complete surgical resection, accessible therapeutic targets and effective tyrosine kinase inhibitors (TKIs) have not completely cured gastrointestinal stromal tumours (GISTs), with most patients suffering from residual tumours and recurrence. The existence of nerve infiltration in GIST provides a way for tumour cells to escape local resection and systemic targeted therapy, which may challenge the previous understanding of its behaviour patterns and inspire the development of more radical excision and more precise targeted therapy. Moreover, tumour dormancy has emerged as a major cause of drug resistance and tumour relapse. Among these pathways, the nerve-tumour regulatory axis GDNF-GFRA1 is activated in GISTs, assists tumour cells in achieving dormancy and protects them from apoptosis under environmental stress by enhancing autophagic flux. The concrete mechanism is that the GDNF-regulating interaction between GFRA1 and the lysosomal calcium channel MCOLN1 activates Ca2+-dependent TFEB signalling. Activated TFEB transcriptionally regulates intracellular lysosome levels, which could achieve feedback upregulation of cellular autophagy flux during TKI treatment. This dormancy-transition axis fills parts of the mechanistic vacancy before the onset of secondary mutations, and strategies for TKIs combined with targeting GFRA1-dependent autophagy have distinct promise as prospective clinical therapies.

Sec23a inhibits the self-renewal of melanoma cancer stem cells via inactivation of ER-phagy

BackgroundThe genesis and developments of solid tumors, analogous to the renewal of healthy tissues, are driven by a subpopulation of dedicated stem cells, known as cancer stem cells (CSCs), that exhibit long-term clonal repopulation and self-renewal capacity. CSCs may regulate tumor initiation, growth, dormancy, metastasis, recurrence and chemoresistance. While autophagy has been proposed as a regulator of the stemness of CSCs, the underlying mechanisms requires further elucidation.MethodsThe CSC component in human melanoma cell lines M14 and A375 was isolated and purified by repetitive enrichments for cells that consistently display anchorage-independent spheroid growth. The stemness properties of the CSCs were confirmed in vitro by the expressions of stemness marker genes, the single-cell cloning assay and the serial spheroid formation assay. Subcutaneous tumor transplantation assay in BALB/c nude mice was performed to test the stemness properties of the CSCs in vivo. The autophagic activity was confirmed by the protein level of LC3 and P62, mRFP-LC3B punta and cytoplasmic accumulation of autolysosomes. The morphology of ER was detected with transmission electron microscopy.ResultsIn the present study, by employing stable CSC cell lines derived from human melanoma cell lines M14 and A375, we show for the first time that Sec23a inhibits the self-renewal of melanoma CSCs via inactivation of ER-phagy. Mechanistically, inhibition of Sec23a reduces ER stress and consequently FAM134B-induced ER-phagy. Furthermore, TCGA data mining and analysis show that Sec23a is a favorable diagnostic and prognostic marker for human skin cutaneous melanoma.ConclusionThis study has elucidated a new mechanism underlying the regulation of autophagy on stemness, i.e. CSCs can exploit the SEC23A/ER-stress/FAM134B/ER-phagy axis for the self-renewal. These observations provide new ideas for exploration of the regulatory network of CSC self-renewal to develop CSCs-based therapy strategies for malignant tumors.1GUvTquPwXFE-w4yWuDKxrVideo

Abstract OT1-08-01: Concurrent versus sequential chemo-endocrine therapy in er positive and her2 negative non-metastatic breast cancer- an open-label, phase III, randomized controlled trial

Abstract Background-Traditionally, endocrine therapy follows chemotherapy for hormone receptor (HR) positive breast cancer (BC) in the adjuvant setting. Concurrent chemo-hormonal therapy fell into disrepute due to previous studies showing a probable, small detriment in survival. (Albain et al, Lancet, 2009; Bedognetti et al, JNCI, 2009; Pico et al, Ann Oncol, 2004) However, the early studies are fraught with biases. The biological rationale was that endocrine therapy is cytostatic, pushing cancer cells into G0 phase which was feared to reduce the efficacy of chemotherapy which is known to act best on rapidly dividing cells. Thus, the two mechanisms of actions were thought to be antagonistic. However, this fear may be irrational and evidence at molecular level is contradictory. The current sequential strategy delays the start of an equally effective treatment modality in HR+ BC patients. Recent studies have shown that concurrent chemo-endocrine therapy is safe in metastatic HR+ setting. (Sledge et al, J Clin Oncol, 2000) One also needs to rethink neoadjuvant strategies in these patients to improve the current dismal pathological complete response (pCR) rates in this subset. (Cortazar et al, Lancet, 2014) Concurrent treatment seems to have improved pCR rate. (Sagiu K et al, Acta Med Okayama, 2015) Here, we describe a phase III, randomized study aimed to evaluate the efficacy of concurrent chemo-endocrine therapy in the adjuvant and neoadjuvant setting. (CTRI/2018/09/015643) Aims and Objectives- The primary objective is to assess the improvement in disease-free survival by administering concurrent versus sequential, (neo) adjuvant chemo-endocrine therapy in HR+, HER2 negative, non-metastatic BC. The secondary objectives are to assess improvement in overall survival, pCR rates, breast conservation rates. Biomarkers of response to treatment and tumour dormancy in HR+ BC will be studied in a subset of patients.Patients and methods-This is a prospective, open label study where non-metastatic, biopsy proven, HR+, HER2- BC patients who warrant chemotherapy in the adjuvant or neoadjuvant setting are considered. The study started accrual in December 2018 and 285 patients are randomized till date. Pregnant or lactating women and those with inflammatory breast carcinoma are excluded. After obtaining informed consent, patients are randomized to receive concurrent versus sequential chemo-endocrine treatment. Patients will receive all chemo and endocrine therapy as per the institutional standard protocols otherwise. Stratification criteria are neoadjuvant vs adjuvant therapy, pre vs postmenopausal status, node positive vs node negative status, 1st gen (anthracyclines alone) versus 2nd gen (including taxanes) chemotherapy. A two-sided log-rank test with an overall sample size of 2316 (2432 with a 5% dropout rate) (1158 in control and 1158 in treatment group) achieves 80% power at a 0.05 significance level to detect a hazard ratio of 0.80 when the proportion surviving in the control group is 0.70. An interim with respect to safety is planned in the protocol. Expected results and conclusion-Ours is a large, prospective trial evaluating the efficacy of concurrent chemo-endocrine therapy in HR+ BC patients. This has the potential to improve pCR rates in the neoadjuvant setting and change the standard of care in the management of HR+ BC patients. The biomarker analysis will help us further understand the biology of HR+ BC and shed light upon tumour dormancy signatures. Citation Format: Shalaka Joshi, Sridevi Murali-Nanavati, Vaibhav Vanmali, Rohini Hawaldar, Mujahid Gafur Shaikh, Mohammad Sadique Ansari, Sushmita Rath, Jaya Ghosh, Seema Gulia, Jyoti Bajpayi, Nita Nair, Vani Parmar, Purvi Thakkar, Garvit Chitkara, Tanuja Shet, Sangeeta Desai, Ayushi Sahay, Sudeep Gupta, Rajendra Badwe. Concurrent versus sequential chemo-endocrine therapy in er positive and her2 negative non-metastatic breast cancer- an open-label, phase III, randomized controlled trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-08-01.

Abstract PD14-05: Portraying tumor evolution of lobular breast cancer through phylogenetic analysis

Abstract Background: Despite therapeutic advancements, a substantial number of patients with treated early-stage invasive lobular carcinoma (ILC) of the breast will still relapse as late as 20 years after the initial tumor diagnosis, thus making follow-up a challenging task. Here, using patient-matched primary and metastatic tumors from patients with ILC, we aimed to decipher the evolution of lobular breast cancer through time and explore metastatic dissemination events and underlying heterogeneity. Materials and Methods: We retrospectively identified 38 patients with metastatic ILC, of which 6 with de novo metastatic disease. In total, 99 formalin-fixed paraffin embedded tissue samples of primary tumor and metastasis, together with well-annotated clinicopathological data, were available. Low coverage whole-genome sequencing was performed to infer somatic copy number aberrations (CNA). Phylogenetic reconstruction was performed with Integer Linear Program for the Copy-Number Tree Problem algorithm. Results: Reconstruction of the phylogenetic trees showed different patterns of dissemination. For patients with multiple metastatic samples sequenced (4/4 patients), the metastases were found to be seeded from a common metastatic precursor. For a subset of patients with multiple primaries (5/10 patients), distant metastases were seeded from specific clones inside the primary tumor. Detailed analysis of known driver genes showed that alterations in common driver genes such as TP53, MYC and CCND1 were shared between primary tumor and metastases in a large proportion of the patients (47%, 32% and 21% of patients respectively) whilst CNA in other driver genes including FGFR2, PTEN or AKT2 among others, were frequently private in the metastases. Interestingly, we observed that in approximately 30% of the patients, the metastases harbored less CNA than the matched primary tumor, resulting in shorter metastatic branches and possibly indicating a decelerated tumor progression. Further analysis of the genomic and clinicopathological characteristics showed that these patients were mostly de novo metastatic (p-value=0.002), metastasizing primarily to the liver or bone and had significantly more aberrations in NF1, AKT1 and FGFR (p-value=0.04, 0.01 and 0.03 respectively), when compared to the rest of the cohort. Finally, most of the patients (63%) had a lower number of CNA accumulated after the metastatic lineage separation compared to the common trunk, implying a late dissemination event. Conclusions: In this study, we described different metastatic dissemination events taking place in ILC. Our analyses allowed us to identify a subset of tumors characterized by slow tumor progression, indicating potential tumor dormancy, as well as evidence of late dissemination evidence for most of the patients, thus highlighting the importance of early detection through cancer screening. These findings further shed light on how ILCs evolves through time and could potentially influence the clinical management of invasive lobular breast cancer. Citation Format: Danai Fimereli, David Venet, Mattia Rediti, David N Brown, Bram Boeckx, Marion Maetens, Samira Majjaj, Ghizlane Rouas, Maria Capra, Giuseppina Bonizzi, Federica Contaldo, Christine Galant, Martine Piccart, Giancarlo Pruneri, Denis Larsimont, Diether Lambrechts, Christine Desmedt, Françoise Rothé, Christos Sotiriou. Portraying tumor evolution of lobular breast cancer through phylogenetic analysis [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD14-05.

Tumor Dormancy: Biologic and Therapeutic Implications.

Metastatic cancer can arise years after treatment of the primary tumor because residual tumor cells can enter dormancy and evade elimination by anti-neoplastic therapies. The mechanisms underlying this phenomenon have been investigated and a number of hypotheses have been proposed. Tumor mass dormancy involves a balance between apoptotic and proliferative cells, keeping a micrometastatic lesion constant in size. This induces a need for blood supply which involves angiogenic dormancy. Cellular dormancy is also considered a mechanism of dormancy, where dormancy is induced due to cells entering a quiescent, reversible, growth-arrested state. In addition to all of these mechanisms, important changes in the tumor microenvironment, including the extracellular matrix, the oxygenation levels of the environment, and endoplasmic reticulum stress, are involved in inducing and maintaining tumor dormancy. Since dormant tumors are commonly known to be resistant to chemotherapy, gaining more knowledge of the mechanism of dormant tumor cells is of importance, as it can lead to the development of future treatment strategies.

Modeling Androgen Deprivation Therapy-Induced Prostate Cancer Dormancy and Its Clinical Implications.

Treatment-induced tumor dormancy is a state in cancer progression where residual disease is present but remains asymptomatic. Dormant cancer cells are treatment-resistant and responsible for cancer recurrence and metastasis. Prostate cancer treated with androgen-deprivation therapy (ADT) often enters a dormant state. ADT-induced prostate cancer dormancy remains poorly understood due to the challenge in acquiring clinical dormant prostate cancer cells and the lack of representative models. In this study, we aimed to develop clinically relevant models for studying ADT-induced prostate cancer dormancy. Dormant prostate cancer models were established by castrating mice bearing patient-derived xenografts (PDX) of hormonal naïve or sensitive prostate cancer. Dormancy status and tumor relapse were monitored and evaluated. Paired pre- and postcastration (dormant) PDX tissues were subjected to morphologic and transcriptome profiling analyses. As a result, we established eleven ADT-induced dormant prostate cancer models that closely mimicked the clinical courses of ADT-treated prostate cancer. We identified two ADT-induced dormancy subtypes that differed in morphology, gene expression, and relapse rates. We discovered transcriptomic differences in precastration PDXs that predisposed the dormancy response to ADT. We further developed a dormancy subtype-based, predisposed gene signature that was significantly associated with ADT response in hormonal naïve prostate cancer and clinical outcome in castration-resistant prostate cancer treated with ADT or androgen-receptor pathway inhibitors.

Parathyroid hormone-related protein in breast cancer bone metastasis.

Parathyroid hormone-related protein (PTHrP) was discovered as the tumor product causing the humoral hypercalcemia of malignancy. Its structural similarity to the hormone, PTH, with 8 of the first 13 amino acids identical, was sufficient to explain the sharing by PTHrP and PTH of a common receptor, PTH1R, although the remainder of the sequences are unique. PTHrP has important roles in development of several organs, including breast and bone, and functions as a paracrine factor postnatally in these and other tissues. In addition to its hormonal role in cancer, PTHrP is produced by two thirds of primary breast cancers and 90% of bone metastases from breast cancer, leading to the concept that its production in bone by breast cancer cells promotes bone resorption, thus favoring tumor establishment and expansion, and an exit from tumor dormancy in bone through downregulation of leukemia inducing factor receptor (LIFR). Cancer production of PTHrP is increased by bone-derived growth factors, with particular attention paid to TGFβ, as well as by promoter-driven transcriptional effects, such as the hedgehog signaling factor, GLI2, and microenvironment effects including changes in underlying stiffness of substrates for cells. Although interest has been focused on PTHrP-induced bone resorption in bone metastasis, a mechanistically separate, protective effect against tumor progression has been proposed. Although there is conflicting mouse data, there are clinical studies suggesting that increased production of PTHrP by breast cancers confers upon them a less invasive phenotype, an effect distinct from the bone resorption-stimulating action that favors bone metastasis.

An overview of chemotoxicity and radiation toxicity in cancer therapy.

While immunotherapy and targeted therapies represent major advances against different types of malignancies, the mainstay of cancer therapy continues to be radiation and surgery for localized disease, and chemotherapy for systemic disease, with the preponderance of chemotherapeutic agents (such as anthracyclines, alkylating agents, and antimetabolites) having been developed decades ago. Combination chemotherapy regimens have changed the natural history of once deadly diseases such as breast and prostate cancer and led to curative regimens in advanced hematological malignancies and testicular cancer. However, while oncologists maintain their focus on disease suppression, and where feasible, disease eradication, obstacles to achieving cure remain, such as tumor dormancy and ultimately disease recurrence, as well as both intrinsic and acquired resistance. In this review, complications of current cancer therapies toward major organs (heart, lung, kidney, gastro-intestinal, neuromuscular, brain, and skin) are emphasized, and efforts to mitigate these complications are described. This is particularly relevant for patients treated with curative intent, where adherence to treatment plan, and avoidance of interruptions in treatment schedule are essential for optimal outcome. Consequently, these patients are treated with an "aggressive" approach, with high tolerance for side effects. However, a deeper understanding of normal tissue toxicity resulting from the different cancer therapies remains an area of unmet medical need that will ultimately lead to improved therapeutic index for current and future therapies, planning for treatment adverse effects, and ultimately improvement in patient satisfaction, compliance and outcome.

DIRAS3: An Imprinted Tumor Suppressor Gene that Regulates RAS and PI3K-driven Cancer Growth, Motility, Autophagy, and Tumor Dormancy.

DIRAS3 is an imprinted tumor suppressor gene that encodes a 26 kDa GTPase with 60% amino acid homology to RAS, but with a distinctive 34 amino acid N-terminal extension required to block RAS function. DIRAS3 is maternally imprinted and expressed only from the paternal allele in normal cells. Loss of expression can occur in a single "hit" through multiple mechanisms. Downregulation of DIRAS3 occurs in cancers of the ovary, breast, lung, prostate, colon, brain, and thyroid. Reexpression of DIRAS3 inhibits signaling through PI3 kinase/AKT, JAK/STAT, and RAS/MAPK, blocking malignant transformation, inhibiting cancer cell growth and motility, and preventing angiogenesis. DIRAS3 is a unique endogenous RAS inhibitor that binds directly to RAS, disrupting RAS dimers and clusters, and preventing RAS-induced transformation. DIRAS3 is essential for autophagy and triggers this process through multiple mechanisms. Reexpression of DIRAS3 induces dormancy in a nu/nu mouse xenograft model of ovarian cancer, inhibiting cancer cell growth and angiogenesis. DIRAS3-mediated induction of autophagy facilitates the survival of dormant cancer cells in a nutrient-poor environment. DIRAS3 expression in dormant, drug-resistant autophagic cancer cells can serve as a biomarker and as a target for novel therapy to eliminate the residual disease that remains after conventional therapy.

Safe Combination of Cisplatin and Metformin Reverts the Malignant Ascites in a Mouse Model to a Solid Tumor by Downregulation of ΔNp63 and Induces Tumor Dormancy via mTOR/ p21 Mechanism

Background: Currently, combination therapy has become the cornerstone of cancer treatment. The combination of different anti-cancer mechanisms can induce tumor cell quiescence. However, toxicity to normal tissue is the major limitation of existing combined drugs. Method: In this experimental study, Ehrlich ascites carcinoma inoculated into mice was targeted with just one dose of cisplatin and later doses of metformin, a safe anti-diabetic drug with an anti-cancer effect, to maintain Ehrlich ascites carcinoma (EAC) cells in the quiescent state and secure a longer survival time without tumor recurrence. Results: The group that underwent dual therapy developed a delayed solid tumor instead of a malignant ascites. The induction of chemo-quiescence in the EAC cells was proven by the downregulation of mechanistic target of rapamycin and the upregulation of cyclin-dependent kinase inhibitor 1 (p21) expressions. Intriguingly, the conversion of free neoplastic cells into a solid tumor was associated with a significant decrease in ΔNp63 immunostaining in EAC cells. Conclusion: Taken together, a single dose of cisplatin followed by metformin doses could overcome the aggressiveness of malignant ascites by the conversion into a solid tumor, induction of chemo-quiescence, and the extension of survival time.

Prostate cancer dormancy and recurrence.

Prostate cancer can progress rapidly after diagnosis, but can also become undetectable after curative intent radiation or surgery, only to recur years or decades later. This capacity to lie dormant and recur long after a patient was thought to be cured, is relatively unique to prostate cancer, with estrogen receptor positive breast cancer being the other common and well-studied example. Most investigators agree that the bone marrow is an important site for dormant tumor cells, given the frequency of bone metastases and that multiple studies have reported disseminated tumor cells in patients with localized disease. However, while more difficult to study, lymph nodes and the prostate bed are likely to be important reservoirs as well. Dormant tumor cells may be truly quiescent and in the G0 phase of the cell cycle, which is commonly called cellular dormancy. However, tumor growth may also be held in check through a balance of proliferation and cell death (tumor mass dormancy). For induction of cellular dormancy, prostate cancer cells respond to signals from their microenvironment, including TGF-β2, BMP-7, GAS6, and Wnt-5a, which result in signals transduced in part through p38 MAPK and pluripotency associated transcription factors including SOX2 and NANOG, which likely affect the epi-genome through histone modification. Clinical use of adjuvant radiation or androgen deprivation has been modestly successful to prevent recurrence. With the rapid pace of discovery in this field, systemic adjuvant therapy is likely to continue to improve in the future.

The role of tumor microenvironment and exosomes in dormancy and relapse.

Recent advancements in the field of cancer have established that the process of metastasis is organ-specific with tumor cell dissemination occurring in the very early stages of disease. Pre-metastatic niches are actively remodeled and transformed by both primary tumor specific factors and by influences from the extracellular matrix.Although improvements in cancer therapies have significantly improved outcomes in patients with early stage disease, the risk of recurrence and relapse leading to mortality remains high. Recent studies have emerged highlighting the influence of dormant tumor cells and exosomes as key players in cancer relapse. In this review we discuss the critical mediators of tumor progression and their link to cancer dormancy, while also exploring possible therapeutics for targeting relapse.

Astrocytic laminin-211 drives disseminated breast tumor cell dormancy in brain.

Although dormancy is thought to play a key role in the metastasis of breast tumor cells to the brain, our knowledge of the molecular mechanisms regulating disseminated tumour cell (DTC) dormancy in this organ is limited. Here, using serial intravital imaging of dormant and metastatic triple-negative breast cancer lines, we identify escape from the single-cell or micro-metastatic state as the rate limiting step towards brain metastasis. We show that every DTC occupies a vascular niche, with quiescent DTCs residing on astrocyte endfeet. At these sites, astrocyte-deposited laminin-211 drives DTC quiescence by inducing the dystroglycan receptor to associate with yes-associated protein (YAP), thereby sequestering it from the nucleus and preventing its pro-metastatic functions. These findings identify a brain-specific mechanism of DTC dormancy and highlight the need for a more thorough understanding of tumor dormancy to develop therapeutic approaches that prevent brain metastasis.

A tumor-derived type III collagen-rich ECM niche regulates tumor cell dormancy.

Cancer cells disseminate and seed in distant organs, where they can remain dormant for many years before forming clinically detectable metastases. Here we studied how disseminated tumor cells (DTCs) sense and remodel the extracellular matrix (ECM) to sustain dormancy. ECM proteomics revealed that dormant cancer cells assemble type III collagen-enriched ECM niche. Tumor-derived type III collagen is required to sustain tumor dormancy as its disruption restores tumor cell proliferation through DDR1-mediated STAT1 signaling. Second harmonic generation two-photon microscopy further revealed that the dormancy-to-reactivation transition is accompanied by changes in type III collagen architecture and abundance. Analysis of clinical samples revealed that type III collagen levels were increased in tumors from lymph node-negative head and neck squamous cell carcinoma (HNSCC) patients compared to lymph node-positive patients. Our data supports that the manipulation of these mechanisms could serve as a barrier to metastasis through DTCs dormancy induction.

Shooting at Moving and Hidden Targets-Tumour Cell Plasticity and the Notch Signalling Pathway in Head and Neck Squamous Cell Carcinomas.

Simple SummaryCancers in the head and neck region are often aggressive and poorly respond to both irradiation or chemotherapy. Chemotherapy is currently limited by a small number of approved drugs. Newer “targeted” drugs, aiming for specific molecules expressed by tumour cells, have not been as beneficial as expected. Research is now investigating new drug targets, involved in the way how tumour cells interact with non-cancer cells from the stroma, the vasculature, and the immune system within the tumour tissues. These highly dynamic processes assist tumour cells to rapidly adapt to any challenges they may encounter during cancer progression or therapy. One such central molecular mechanism, regulating increased tumour cell plasticity, is the Notch signalling pathway. We currently are only beginning to understand the complex interactions of Notch receptors with their ligands, in a broad spectrum of tumour and tumour-associated cells, and how such interactions could represent targets for cancer chemotherapy and personalized medicine.Head and Neck Squamous Cell Carcinoma (HNSCC) is often aggressive, with poor response to current therapies in approximately 40–50% of the patients. Current therapies are restricted to operation and irradiation, often combined with a small number of standard-of-care chemotherapeutic drugs, preferentially for advanced tumour patients. Only very recently, newer targeted therapies have entered the clinics, including Cetuximab, which targets the EGF receptor (EGFR), and several immune checkpoint inhibitors targeting the immune receptor PD-1 and its ligand PD-L1. HNSCC tumour tissues are characterized by a high degree of intra-tumour heterogeneity (ITH), and non-genetic alterations that may affect both non-transformed cells, such as cancer-associated fibroblasts (CAFs), and transformed carcinoma cells. This very high degree of heterogeneity likely contributes to acquired drug resistance, tumour dormancy, relapse, and distant or lymph node metastasis. ITH, in turn, is likely promoted by pronounced tumour cell plasticity, which manifests in highly dynamic and reversible phenomena such as of partial or hybrid forms of epithelial-to-mesenchymal transition (EMT), and enhanced tumour stemness. Stemness and tumour cell plasticity are strongly promoted by Notch signalling, which remains poorly understood especially in HNSCC. Here, we aim to elucidate how Notch signal may act both as a tumour suppressor and proto-oncogenic, probably during different stages of tumour cell initiation and progression. Notch signalling also interacts with numerous other signalling pathways, that may also have a decisive impact on tumour cell plasticity, acquired radio/chemoresistance, and metastatic progression of HNSCC. We outline the current stage of research related to Notch signalling, and how this pathway may be intricately interconnected with other, druggable targets and signalling mechanisms in HNSCC.