[An anatomical road map of the parapharyngeal internal carotid artery in lateral and endoscopic ventral approaches].

Objective:To describe the road map of the lateral and endoscopic ventral approaches for the pharyngeal segment of the internal carotid artery, propose a sub-segmentation scheme, systematically and comprehensively understand its anatomical details and relationships with the surrounding structures. Methods:Five fresh cadaveric head specimens（10 sides in total） were dissected through lateral and endoscopic ventral approaches to evaluate the anatomical details of the parapharyngeal internal carotid artery and its relationship with the surrounding structures. Results:From the bifurcation of the common carotid artery to the vertical part of the internal carotid artery, alongside the direction of blood flow, the parapharyngeal internal carotid artery passes through four distinct anatomical tissues. Based on this, the parapharyngeal internal carotid artery can be divided into four sub-segments: nerve, muscle, fascia and osseous sub-segments. The boundaries and important adjacent structures of each segment are described in detail. Conclusion:The anatomical road map of the parapharyngeal internal carotid artery and the sub-segmentation scheme serving as a practical guide to navigate modular endoscopic skull base surgery of the parapharyngeal space while reduce the risk of internal carotid artery injury.

Metastatic Patterns and Prognosis of Patients with Sinonasal Carcinoma: A Population-Based Study.

INTRODUCTION: The aim of this study was to summarize the incidence, risk factors, and prognostic factors of distant metastasis of sinonasal carcinoma. METHODS: We collected data for patients diagnosed with sinonasal carcinoma from 2010 to 2015 from the SEER database and analyzed the risk factors for distant metastasis via univariate and multivariate logistic regression analysis. In addition, univariate and multivariate Cox regression analysis models were used to describe the factors related to the overall survival of patients with distant metastasis. RESULTS: A total of 2,255 patients were included in the study, including 86 in the distant metastasis group and 2,169 in the nondistant metastasis group. In the univariate and multivariate logistic regression analyses, we found that the risk factors affecting distant metastasis were poorly differentiated tumor grade (HR = 1.932, 95% CI: 1.082-3.452, p = 0.026), advanced T stage (T3-T4) (HR = 4.302, 95% CI: 2.047-9.039, p < 0.001), and advanced N stage (HR = 3.093, 95% CI: 1.911-5.005, p < 0.001). Moreover, elderly patients had a poorer prognosis than young patients (HR = 1.792, 95% CI: 1.096-2.931, p = 0.02) and that surgical treatment improved the survival rate of tumor patients with distant metastasis (HR = 0.450, 95% CI: 0.247-0.821, p = 0.009). CONCLUSION: Tumor grade, T stage, and N stage are risk factors for distant metastasis in sinonasal carcinoma, while an age of less than 65 years and surgery were positive prognostic factors for sinonasal carcinoma patients with distant metastasis.

[Effects of orofacial myofunctional therapy on postoperative outcomes of upper airway surgery for adults with severe obstructive sleep apnea].

Objective:To investigate the effect of orofacial myofunctional therapy on the clinical efficacy of upper airway surgery for adults with severe obstructive sleep apnea（OSA）. Methods:A total of 48 patients with OSA who underwent upper airway surgery in the Shenzhen Second People's Hospital from June 2020 to September 2021 were included in this study. These patients were randomly divided into the combination group（21 cases） and the surgery group（27 cases）. The effective rate, AHI, minimum blood oxygen saturation, snoring events and Epworth sleepiness scale scores at 6 months after operation were compared and analyzed between the two groups. Results:The proportions of AHI, LSaO2, snoring events, and total snoring time in the combined group at 6 months after operation were（14.77±9.15） times/h, （81.19±6.52）%, （172.43±73.67） times, and（13.16±6.02）%. The proportion of AHI, LSaO2, snoring events, and total snoring time in surgical group at 6 months after operation was（23.87±10.6） times/h, （80.78±4.88）%, （235.81±83.23） times, （17.58±5.94）%. Compared with preoperative 6 months after operation, the proportion of AHI, snoring events, and total snoring time was significantly decreased, and LSaO2was significantly increased, and the differences were statistically significant（P<0.05）. The time of snoring and the proportion of snoring to time were significantly improved compared with those in the simple operation group, and the differences were statistically significant（P<0.05）. Conclusion:This study verified that orofacial myofunctional therapy can improve the clinical efficacy after upper airway surgery for adults with severe obstructive sleep apnea.

Lenvatinib for effectively treating antiangiogenic drug-resistant nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) clinical trials show that antiangiogenic drugs (AADs) fail to achieve the expected efficacy, and combining AAD with chemoradiotherapy does not show superiority over chemoradiotherapy alone. Accumulating evidence suggests the intrinsic AAD resistance in NPC patients with poorly understood molecular mechanisms. Here, we describe NPC-specific FGF-2 expression-triggered, VEGF-independent angiogenesis as a mechanism of AAD resistance. Angiogenic factors screening between AAD-sensitive cancer type and AAD-resistant NPC showed high FGF-2 expression in NPC in both xenograft models and clinical samples. Mechanistically, the FGF-2-FGFR1-MYC axis drove endothelial cell survival and proliferation as an alternative to VEGF-VEGFR2-MYC signaling. Genetic knockdown of FGF-2 in NPC tumor cells reduced tumor angiogenesis, enhanced AAD sensitivity, and reduced pulmonary metastasis. Moreover, lenvatinib, an FDA recently approved multi-kinase inhibitor targeting both VEGFR2 and FGFR1, effectively inhibits the tumor vasculature, and exhibited robust anti-tumor effects in NPC-bearing nude mice and humanized mice compared with an agent equivalent to bevacizumab. These findings provide mechanistic insights on FGF-2 signaling in the modulation of VEGF pathway activation in the NPC microenvironment and propose an effective NPC-targeted therapy by using a clinically available drug.

Prognostic Nomograms for Predicting Overall Survival and Cancer-Specific Survival in Patients with Head and Neck Mucosal Melanoma.

Background: Accurate forecasting of the risk of death is crucial for people living with head and neck mucosal melanoma (HNMM). We aimed to establish and validate an effective prognostic nomogram for HNMM. Methods: Patients with HNMM who underwent surgery between 2010 and 2015 were selected from the Surveillance, Epidemiology, and End Results (SEER) database for model construction. After eliminating invalid and missing clinical information, 288 patients were ultimately identified and randomly divided into a training cohort (199 cases) and a validation cohort (54 cases). Univariate and multivariate Cox proportional hazards regression analyses were performed in the training cohort to identify prognostic variables. Independent influencing factors were used to build the model. Through internal verification (training cohort) and external verification (validation cohort), the concordance indexes (C-indexes) and calibration curves were used to evaluate the predictive value of the nomogram. Results: For the training cohort, five independent risk predictors, namely age, location, T stage, N stage, and surgery, were selected, and nomograms with estimated 1- and 3-year overall survival (OS) and cancer-specific survival (CSS) were established. The C-index showed that the predictive performance of the nomogram was better than that of the TNM staging system and was internally verified (through the training queue: OS: 0.764 vs 0.683, CSS: 0.783 vs 0.705) and externally verified (through the verification queue: OS: 0.808 vs 0.644, CSS: 0.823 vs 0.648). The calibration curves also showed good agreement between the prediction based on the nomogram and the observed survival rate. Conclusion: The nomogram prediction model can more accurately predict the prognosis of HNMM patients than the traditional TNM staging system and may be beneficial for guiding clinical treatment.

Resection of small acoustic neuroma using the transcanal transvestibular endoscopic approach.

We evaluated the outcomes of resection of small acoustic neuromas using the transcanal transvestibular endoscopic approach. Two patients with a small acoustic neuroma were treated using this approach. The sizes of the tumors were 11 × 6 mm and 12 × 10 mm. Both tumors were removed completely without residual tumor tissue, and damage to the facial nerve and cochlear nerve was avoided. No patients developed postoperative vertigo, aggravation of postoperative facial paralysis, severe pain, or permanent postoperative complications. The patients were followed up for 6 months, and none developed recurrence. Resection of small acoustic neuromas by the transcanal transvestibular endoscopic approach is a simple and safe technique that achieves excellent functional results.

[Ultrasound measurement of upper airway related indicators and patients with obstructive sleep apnea hypopnea correlation study of disease severity].

Objective:To compare the difference of upper airway anatomy between non-obstructive sleep apnea（OSA） patients and OSA patients, and to analyse the correlation between upper airway anatomy and the disease severity based on the upper airway ultrasound examination. Methods:Eighty-five OSA patients （OSA group） and 36 non-OSA subjects （non-OSA group） who were admitted to the Second Hosipital of Shenzhen from January 2021 to May 2021 were recruited to perform upper airway ultrasound measurement. The airway anatomical parameters were compared and analyzed by t-test. The Spearman correlation analysis was performed on the ultrasound measurement values of OSA patients with the apnea-hypopnea index （AHI） and minimum blood oxygen saturation （ LSaO2）. Results:There were statistically significant differences in BMI, the distance between the soft and hard palate junction and the hyoid bone, the angle between the hard palate and the soft palate, and the angle between the hyoid bone and the hard palate between the OSA group and the non-OSA group（P<0.001，respectively）; For 85 cases of OSA， correlation analysis between the patient's upper airway B-ultrasound measurements and AHI and LSaO2 showed that the distance from the soft and hard palate junction to the mandible, the distance from the soft and hard palate junction to the hyoid bone, the thickness of the tongue（longitudinal section）, and the thickness of the soft palate（longitudinal section）are positively correlated with AHI（r=0.3758, 0.4619, 0.3227, 0.2738, P<0.05, respectively）; the distance from the soft and hard palate to the mandible, the distance from the soft and hard palate to the hyoid bone, the width of tongue（transverse section），and the tongue thickness（longitudinal section） are negatively correlated with LSaO2（r=-0.3566, -0.5470, -0.3168, -0.3098, P<0.05, respectively）; the angle between the hard palate and the soft palate is negatively correlated with AHI（r=-0.2262, P<0.05）; the angle between the hyoid bone and the hard palate is positively correlated with AHI and negatively correlated with LSaO2（r=0.2889, -0.3351, P<0.01）. Conclusion:The upper airway related anatomical parameters based on ultrasound measurement, such as the distance from the soft and hard palate junction to the mandible, the distance from the soft and hard palate junction to the hyoid bone, the angle between the hyoid bone and the hard palate, and the angle between the hard palate and the soft palate, etc.， are associated with the disease severity in OSA patients. The correlation may be used as a potential objective indicator to evaluate the severity of patients with OSA.

Retinoblastoma cell-derived Twist protein promotes regulatory T cell development.

BACKGROUND: The development of tumor tissue-infiltrating regulatory T cell (Treg) is incompletely understood. This study investigates the role of retinoblastoma cell (Rbc)-derived Twist­related protein 1 (Twist) in the Treg development. METHODS: The surgically removed Rb tissues were collected. Rbcs were cultured with CD4+ T cells to assess the role of Rbc-derived Twist in the Treg generation. RESULTS: We found that more than 90% Rbcs expressed Twist. Foxp3+ Tregs were detected in the Rb tissues that were positively correlated with the Twist expression in Rbcs, negatively associated with Rb patient survival and sight survival. Treating Rbcs with hypoxia promoted the Twist expression that could be detected in the cytoplasm, nuclei and on the cell surface. Twist activated CD4+ T cells by binding the TLR4/myeloid differentiation factor 2 complex and promoted the transforming growth factor-ß-inducible early gene 1 product and Foxp3 expression. These Rbc-induced Foxp3+ Tregs showed immune-suppressive function on CD8+ T cell proliferation. CONCLUSIONS: Rbcs express Twist, that induces IL-4+ Foxp3+ Tregs; the latter can inhibit CD8+ cytotoxic T cell activities. Therefore, Twist may play an important role in the pathogenesis of Rb.

Obesity-Related Fatty Acid and Cholesterol Metabolism in Cancer-Associated Host Cells.

Obesity-derived disturbances in fatty acid and cholesterol metabolism are linked to numerous diseases, including various types of malignancy. In tumor cells, metabolic alterations have been long recognized and intensively studied. However, metabolic changes in host cells in the tumor microenvironment and their contribution to tumor development have been largely overlooked. During the last decade, research advances show that fatty acid oxidation, cholesterol metabolism, and lipid accumulation play critical roles in cancer-associated host cells such as endothelial cells, lymph endothelial cells, cancer-associated fibroblasts, tumor-associated myeloid cells, and tumor-associated lymphocytes. In addition to anti-angiogenic therapies and immunotherapy that have been practiced in the clinic, metabolic regulation is considered another promising cancer therapy targeting non-tumor host cells. Understanding the obesity-associated metabolism changes in cancer-associated host cells may ultimately be translated into therapeutic options that benefit cancer patients. In this mini-review, we briefly summarize the lipid metabolism associated with obesity and its role in host cells in the tumor microenvironment. We also discuss the current understanding of the molecular pathways involved and future perspectives to benefit from this metabolic complexity.

Fat Wasting Is Damaging: Role of Adipose Tissue in Cancer-Associated Cachexia.

Loss of body weight, especially loss of adipose tissue and skeletal muscle weight, characterizes cancer-associated cachexia (CAC). Clinically, therapeutic options for CAC are limited due to the complicated signaling between cancer and other organs. Recent research advances show that adipose tissues play a critical role during thermogenesis, glucose homeostasis, insulin sensitivity, and lipid metabolism. Understanding the adipocyte lipolysis, the formation of beige adipocytes, and the activation of brown adipocytes is vital for novel therapies for metabolic syndromes like CAC. The system-level crosstalk between adipose tissue and other organs involves adipocyte lipolysis, white adipose tissue browning, and secreted factors and metabolites. Novel CAC animal models and accumulating molecular signaling knowledge have provided mechanisms that may ultimately be translated into future therapeutic possibilities that benefit CAC patients. This mini review discusses the role of adipose tissue in CAC development, mechanism, and therapy.

Involvement of the TGF-ß1 pathway in caveolin-1-associated regulation of head and neck tumor cell metastasis.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most frequent malignancy with a 5-year survival rate of 54%. Therefore, disease management improvement is required. The present study aimed to assess the role of caveolin-1 (Cav-1) in the metastasis of head and neck tumor cells. Short hairpin RNA was used to silence Cav-1 expression in Tu686 cells. Proliferation, migration, invasion, morphology and the levels of effector proteins were assessed in cells. Upon Cav-1 silencing, E-cadherin levels were decreased, while vimentin levels were significantly increased. Cell migration, quantified by wound healing and Transwell assays, was significantly increased. Meanwhile, Cav-1 and transforming growth factor ß1 (TGF-ß1) receptor were identified to be co-localized. In addition, Cav-1-knockdown resulted in increased phosphorylation of SMAD family member 2 (P<0.05), a downstream effector of TGF-ß signaling. In addition, there was a mutual regulation, with increasing TGF-ß1 levels leading to a dose-dependent decrease of Cav-1 expression levels (P<0.05). These findings indicate that Cav-1 inhibits cell metastasis in HNSCC, suggesting the involvement of the TGF-ß signaling pathway.

p38α Mitogen-Activated Protein Kinase Is a Druggable Target in Pancreatic Adenocarcinoma.

p38 mitogen-activated protein kinases are signaling molecules with major involvement in cancer. A detailed mechanistic understanding of how p38 MAPK family members function is urgently warranted for cancer targeted therapy. The conformational dynamics of the most common member of p38 MAPK family, p38α, are crucial for its function but poorly understood. Here we found that, unlike in other cancer types, p38α is significantly activated in pancreatic adenocarcinoma samples, suggesting its potential for anti-pancreatic cancer therapy. Using a state of the art supercomputer, Anton, long-timescale (39 µs) unbiased molecular dynamics simulations of p38α show that apo p38α has high structural flexibility in six regions, and reveal potential catalysis mechanism involving a "butterfly" motion. Moreover, in vitro studies show the low-selectivity of the current p38α inhibitors in both human and mouse pancreatic cancer cell lines, while computational solvent mapping identified 17 novel pockets for drug design. Taken together, our study reveals the conformational dynamics and potentially druggable pockets of p38α, which may potentiate p38α-targeting drug development and benefit pancreatic cancer patients.

Visualisation of the vomerovaginal canal during endonasal transpterygoid approaches and CT imaging diagnosis.

The vomerovaginal canal (VVC) and palatovaginal canal (PVC) are two canals that open forward to the posterior wall of the pterygopalatine fossa (PPF). Although the anatomy and computed tomography (CT) appearances of the PVC have been well studied, the VVC has been rarely reported, especially in endoscopic examinations. Some studies have even failed to distinguish the PVC from the VVC on CT images. The purpose of this study was to demonstrate the anatomy of the VVC on endoscopy and reveal its differences from the PVC, and to analyse the relative positions of the VVC, PVC, and pterygoid canal on CT images. Ten dry skull bases were studied to observe the structures involved in the formation of the VVC. Dissection of four cadaveric heads was performed to demonstrate the anatomy of the VVC on endoscopy. Coronal CT image analysis in 70 patients was conducted to evaluate the distances and relative positions between the VVC, PVC, and pterygoid canal. The PVC and VVC were also compared on axial CT images. The osteological study showed the top wall of the VVC was the antero-inferior wall of the sphenoid sinus. The VVC may be a helpful landmark in endoscopic endonasal transpterygoid approaches. Steps and discrimination in the dissections of the VVC and PVC were described. The interval between the PVC and VVC could be observed on both coronal and axial CT images. The coronal CT images of patients showed differences in the positions and distances among the three canals at both the anterior and posterior apertures of the PVC. The VVC can be easily mistaken for the PVC if its existence is not suspected. The anatomical morphologies and trajectories of the VVC and PVC differed on both nasal endoscopy and CT. The existence of the VVC should be considered during surgery and CT diagnosis within this area.

Combined transoral and endoscopic approach for cervical spine tumor resection.

This study aimed to explore the feasibility and clinical effectiveness of a combined transoral and endoscopic approach for the removal of benign cervical spine tumors.First, we obtained detailed anatomical measurements of the atlantoaxial joint from 20 fresh cadaveric specimens and performed simulated surgeries with the combined transoral and endoscopic approach on 10 cadaveric specimens. Then, we applied the combined approach for the resection of benign cervical spine tumors in 8 patients at our hospital from October 2013 to October 2015. All patients underwent enhanced axial, coronal, and sagittal computed tomography (CT) examination before and after surgery. Preoperative 3-dimensional (3D) reconstruction and printing models were used in 5 cases.On the basis of CT measurements of fresh cadaveric atlantoaxial anatomy and practical experiences from simulated surgeries on the cadaveric specimens with latex perfusion, cervical tumors were completely removed from 8 patients without complications. The average surgery time was 73 minutes, and the average intraoperative bleeding volume was 34 mL. The average hospital stay was 6.5 days. The average NRS score of patients was 2.25 points at 3 days postoperation. At the 12-month postoperative follow-up, the atlantoaxial vertebral bone had been largely repaired, and no recurrence was observed by cervical CT examination.The combined transoral and endoscopic approach could be used safely and effectively to excise cervical spine tumors with substantial advantages, including direct surgical access, relatively simple operation, short operative time, quick postoperative recovery, a reliable curative effect, and few complications.

A morphometric study of the structures bordering the infra-cochlear corridor - Relevant for endoscopic/microscopic ear surgery.

Application of surgical endoscope, used alone or in combination with the surgical microscope, for the operative management of ear and temporal bone conditions may allow improved access and clearance of disease. Preservation of normal structures may also be improved. As the use of this tool is increasing, the need for better understanding of the anatomy of the ear is becoming evident. This is particularly so for endoscopic surgery aiming at removal of lesions involving the infra-cochlear corridor and/or petrous apex. Human temporal bone-derived labyrinth casts (molds), originally made for endolymphatic duct and sac analysis which genuinely represent the membranous labyrinth and its adjacent soft tissues, were morphometrically analyzed in terms of the anatomic relations between structures in and around the infra-cochlear corridor. The distance between the petrous carotid artery (PCA) and the basal turn of the cochlea, the distance between PCA and infra-cochlear vein (ICV)/cochlear aqueduct (CA), and the distance between the lower surface of basal cochlear turn and the point where the carotid artery and jugular vein (JV) meet close to the jugular foramen, were measured to be around 1.3 mm, 6 mm and 8 mm respectively, thus constituting an approximate 6 × 8 mm2 infra-cochlear corridor. This analysis and further study with larger samples might be helpful for operation via this corridor led to the petrous apex where cholesterol granuloma, cholesteatoma and other lesions are not uncommon.

The Key Transcription Factor Expression in the Developing Vestibular and Auditory Sensory Organs: A Comprehensive Comparison of Spatial and Temporal Patterns.

Inner ear formation requires that a series of cell fate decisions and morphogenetic events occur in a precise temporal and spatial pattern. Previous studies have shown that transcription factors, including Pax2, Sox2, and Prox1, play important roles during the inner ear development. However, the temporospatial expression patterns among these transcription factors are poorly understood. In the current study, we present a comprehensive description of the temporal and spatial expression profiles of Pax2, Sox2, and Prox1 during auditory and vestibular sensory organ development in mice. Using immunohistochemical analyses, we show that Sox2 and Pax2 are both expressed in the prosensory cells (the developing hair cells), but Sox2 is later restricted to only the supporting cells of the organ of Corti. In the vestibular sensory organ, however, the Pax2 expression is localized in hair cells at postnatal day 7, while Sox2 is still expressed in both the hair cells and supporting cells at that time. Prox1 was transiently expressed in the presumptive hair cells and developing supporting cells, and lower Prox1 expression was observed in the vestibular sensory organ compared to the organ of Corti. The different expression patterns of these transcription factors in the developing auditory and vestibular sensory organs suggest that they play different roles in the development of the sensory epithelia and might help to shape the respective sensory structures.

Extension of the Clinical Significance of the "Cog".

OBJECTIVE: To study the clinical anatomy of the epitympanum, the attic, and its medial wall, to try to discover a new clinical operation-related anatomical landmark, and to investigate the adjacent anatomical relationship with this landmark. MATERIALS AND METHODS: Eight donor temporal bone specimens were dissected endoscopically. For 29 healthy persons (17 males and 12 females), CT images of the temporal bone (57 ears) were taken, 3-dimensional (3-D) reconstruction and multidimensional plane reconstruction were performed, and identification and assessment of 3-D spatial relationships between any 2 of these complex structures were done. RESULTS: 3-D images of the temporal bone structures including the facial nerve, the cochlea, the semicircular canal, and the brain plate were reconstructed and shown in detail. We discovered a new clinical surgery-related anatomical landmark (the "cog" tangent and the trailing edge of the cog). Based on the tangent and the trailing edge of the cog, we quantified the anatomical relationship between it and its neighboring important structures. CONCLUSION: Based on endoscopic anatomy and the temporal bone spiral CT 3-D structure reconstruction of the epitympanum, the attic, and the adjacent structures, we found an extension of the clinical significance the cog. Quantification of the adjacent anatomical relationship of this landmark is very important for otology microsurgical operation.

Cancer Lipid Metabolism Confers Antiangiogenic Drug Resistance.

Intrinsic and evasive antiangiogenic drug (AAD) resistance is frequently developed in cancer patients, and molecular mechanisms underlying AAD resistance remain largely unknown. Here we describe AAD-triggered, lipid-dependent metabolic reprogramming as an alternative mechanism of AAD resistance. Unexpectedly, tumor angiogenesis in adipose and non-adipose environments is equally sensitive to AAD treatment. AAD-treated tumors in adipose environment show accelerated growth rates in the presence of a minimal number of microvessels. Mechanistically, AAD-induced tumor hypoxia initiates the fatty acid oxidation metabolic reprogramming and increases uptake of free fatty acid (FFA) that stimulates cancer cell proliferation. Inhibition of carnitine palmitoyl transferase 1A (CPT1) significantly compromises the FFA-induced cell proliferation. Genetic and pharmacological loss of CPT1 function sensitizes AAD therapeutic efficacy and enhances its anti-tumor effects. Together, we propose an effective cancer therapy concept by combining drugs that target angiogenesis and lipid metabolism.

A Zebrafish Model Discovers a Novel Mechanism of Stromal Fibroblast-Mediated Cancer Metastasis.

Purpose: Cancer metastasis can occur at the early stage of tumor development when a primary tumor is at the microscopic size. In particular, the interaction of malignant cells with other cell types including cancer-associated fibroblasts (CAF) in promoting metastasis at the early stage of tumor development remains largely unknown. Here, we investigated the role of CAFs in facilitating the initial events of cancer metastasis when primary tumors were at microscopic sizes.Experimental Design: Multicolor-coded cancer cells and CAFs were coimplanted into the transparent zebrafish body and metastasis at a single-cell level was monitored in living animals. Healthy fibroblasts, tumor factor-educated fibroblasts, and CAFs isolated from various tumors were tested for their ability to facilitate metastasis.Results: We showed that CAFs promoted cancer cell metastasis at the very early stage during primary tumor development. When a primary tumor was at the microscopic size consisting of a few hundred cells, CAFs were able to hijack cancer cells for dissemination from the primary site. Surprisingly, a majority of metastatic cancer cells remained in tight association with CAFs in the circulation. Furthermore, stimulation of non-metastasis-promoting normal fibroblasts with TGF-B, FGF-2, HGF, and PDGF-BB led to acquisition of their metastatic capacity.Conclusions: Cancer metastasis occurs at the very early stage of tumor formation consisting of only a few hundred cells. CAFs are the key cellular determinant for metastasis. Our findings provide novel mechanistic insights on CAFs in promoting cancer metastasis and targeting CAFs for cancer therapy should be aimed at the early stage during cancer development. Clin Cancer Res; 23(16); 4769-79. ©2017 AACR.