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PubMed2003

An analysis of cervical lymph nodes metastasis in oral squamous cell carcinoma. Relationship between grade of histopathological malignancy and lymph nodes metastasis.

Cervical lymph nodes metastasis is well known to be an indicator of poor prognosis in patients with oral cancer. This study was considered 38 patients of oral squamous cell carcinoma who were treated at our department from 1993 to 1997. Histological malignancy of initial biopsy in the pretreatment period was evaluated by Anneroth's classification. The relationship of degree of histological malignancy with cervical lymph nodes metastasis were analysed in this study. Metastasis in the cervical lymph nodes was histologically confirmed in 17 out of 38 cases (44.7%). The metastasis located predominantly in the submandibular nodes and superior internal jugular nodes. According to T classification, the rate of metastasis in the cervical lymph nodes in T1 and T2 cases was around 30%, while the rate in T3 and T4 cases tended to be as high as around 60%. However, there was no significant difference. A significant relation was evident between the degree of histological malignancy and metastasis in the cervical lymph nodes (P< 0.01), indicating that the histological malignancy could be served as a predictor for metastasis in the cervical lymph nodes. Among the six parameters, a significant difference was observed only in the degree of keratinization and the mode of invasion (P< 0.05). When the sum of the degree of histological malignancy exceeds 15, metastasis in the cervical lymph nodes should be considered.

Carcinoma, Squamous Cell↗
PubMed1995

[Molecular biological mechanism of cancer metastasis and the prediction of metastasis in clinical cases].

An outline of the mechanism of cancer metastasis is presented from a molecular biological point of view, and the present state and future possibility of prediction about cancer metastasis in clinical cases is described. Cancer metastasis is developed through multiple steps. With the progress of studies on the mechanism of metastasis, the effort to predict cancer metastasis in clinical cases has progressed. Metastasis is formed in concern with many factors, so it may be highly difficult to explain clinical metastasis by a single factor. It will be important to comprehensively put many factors into consideration. For the preoperative diagnosis of the potential of metastasis, examination of specimens from endoscopic biopsy or blood serum will become more important.

Cell Adhesion Molecules↗
PubMed1984

Spontaneous metastasis of highly metastatic variants of mouse tumors and the effect of drugs on the metastasis.

Spontaneous metastasis of highly metastatic variants, B16 melanoma BL-6 and colon adenocarcinoma 26 NL-22, was examined. Tumor cells were inoculated into the right front footpad and the original tumors were removed by amputation of the forelimb at an appropriate time after tumor inoculation. Spontaneous lymph node and lung metastases occurred with B16 BL-6 and spontaneous lung metastasis occurred with NL-22. Analysis of the time-dependent formation of lymph node and lung metastases of BL-6 indicated that lung metastasis could be formed after the lymph node metastasis. Metastasis is influenced by the mouse strain, and both inbred and F1 hybrid mice of syngeneic origin could be used as host animals. By using these metastatic variants, two spontaneous metastasis systems were established. In order to evaluate the systems, the effects of 5-fluorouracil (5-FU) and adriamycin (ADM) were examined. 5-FU was effective against the metastases of both tumors, and ADM was moderately effective against B16 BL-6 metastasis.

Adenocarcinoma↗
PubMed1994

Inhibition of metastasis of Lewis lung carcinoma by a synthetic peptide within growth factor-like domain of urokinase in the experimental and spontaneous metastasis model.

Four synthetic peptides (residues 20-30 and 17-34) within the growth factor-like domain (GFD) of murine and human urokinase-type plasminogen activator (uPA) were examined to determine whether they inhibit production of experimental and spontaneous lung metastasis by murine Lewis lung carcinoma (3LL) cells. In an in vivo experimental metastasis assay, which determines mainly the later steps of the metastatic migration process (extravasation from the bloodstream and then growth into pulmonary tumor), none of the peptides introduced by i.v. single co-injection into syngeneic C57B1/6 mice inhibited pulmonary metastasis, when 3LL cells were pre-incubated with the peptides followed by i.v. co-injection of the peptide and cells. In addition, none of the peptides, when injected i.p. daily for 7 days after i.v. tumor cell inoculation, reduced the number of lung tumor colonies. In a second in vivo assay that measures metastasis from a primary tumor (spontaneous metastasis model), multiple i.p. injections of the mouse peptide 17-34 for 7 days after s.c. tumor cell inoculation significantly inhibited metastatic lung tumor colonization in a dose-dependent manner, whereas human peptide 17-34 had no effect. Mouse and human peptide 20-30 had no effect either. The inhibition of lung metastasis was not due to direct antitumor effects of mouse peptide 17-34. Our results indicate that occupation of uPA receptors on 3LL cells by the enzymatically inactive mouse peptide 17-34 or prevention of rebinding of uPA synthesized by tumor cells to their receptor specifically reduced tumor cell invasion and formation of metastasis and that uPA may regulate more efficiently the mechanism involved in the entry of tumor cells into vascular circulation than extravasation during the metastatic process.

Amino Acid Sequence↗
PubMed1995

Inhibition of metastasis of Lewis lung carcinoma by urinary trypsin inhibitor in experimental and spontaneous metastasis models.

A purified human urinary trypsin inhibitor (UTI) and its related synthetic peptides were examined to determine whether they could inhibit production of experimental and spontaneous lung metastases by murine Lewis lung carcinoma (3LL) cells. Three peptides, peptide I, peptide 2 and peptide 3, representing the amino acid sequences within the UTI molecule, were synthesized. UTI and peptide 2 inhibited human leukocyte elastase (HLE). UTI and peptide 3 specifically inhibited human and murine plasmin activity. Peptide I had essentially no inhibitory activity. In an in vivo spontaneous metastasis model, multiple s.c. injections of UTI or peptide 3 for 7 days immediately after s.c. tumor cell inoculation significantly inhibited the formation of lung metastasis in C57BL/6 mice in a dose-dependent manner. UTI reduced lung tumor colonization more effectively than peptide 3. Peptides 1 and 2, however, did not affect the formation of lung metastasis. Inhibition of lung metastasis was not due to direct anti-tumor effects of UTI and peptide 3. In an in vivo experimental metastasis assay, multiple s.c. injections of UTI for 7 days after i.v. tumor cell inoculation inhibited metastatic lung tumor colonization, while peptide 3 did not affect metastasis. Peptides 1 and 2 did not affect the formation of lung metastasis. When examined with an in vitro assay system using a modified Boyden chamber, UTI and peptide 3 suppressed the invasion of tumor cells through Matrigel. UTI and peptide 3 inhibited neither cell proliferation nor the binding of tumor cells to Matrigel and showed no significant suppression of chemotactic migration of tumor cells to fibronectin. Our results suggest that UTI efficiently regulates the mechanism involved in not only the entry into vascular circulation of tumor cells (intravasation, though, at least in part, inhibition of the proteolytic enzyme plasmin) but also the extravasation step of the metastatic process.

Amino Acid Sequence↗
PubMed2003

Identification of metastasis-associated proteins by proteomic analysis and functional exploration of interleukin-18 in metastasis.

Very little is currently known about mechanisms underlying cancer metastasis. In the present study, metastasis-associated proteomes were separated and identified by comparative proteomic analysis, and the metastasis-related function of candidate protein interleukin-18 (IL-18) was further elucidated. First, a pair of highly and poorly metastatic sublines (termed PLA801D and PLA801C, respectively), originating from the same parental PLA801 cell line, was identified by spontaneous tumorigenicity and metastasis in vivo and characterized by metastatic phenotypes analysis in vitro. Subsequently, a proteomic approach was used to compare the protein expression profiles between PLA801C and PLA801D sublines. Eleven proteins were identified and further verified by one-dimensional Western blotting, Northern blot and/or semiquantitative reverse transciptase polymerase chain reaction analysis. Compared with those in poorly metastatic PLA801C subline, cytokeratin 18, tissue transglutaminase, Rho GDP-dissociation inhibitor 1, tropomyosin, fibroblast type, IL-18 and annexin I were significantly up-regulated, while protein disulfide isomerase, heat shock protein 60, peroxiredoxin 1, chlorine intracellular channel protein 1 (CLI1) and creatine kinase, B chain were significantly down-regulated in the highly metastatic PLA801D subline. Intriguingly, all the identified candidate proteins except for CLI1 have been shown to be somehow associated with distinct aspects of tumor metastasis such as cell growth, motility, invasion, adhesion, apoptosis and tumor immunity, etc. Considering that IL-18 was present in highly metastatic PLA801D but absent in poorly metastatic PLA801C, the association of IL-18 with metastasis was further elucidated by introducing IL-18 sense/IL-18 antisense into PLA801C/PLA801D sublines simultaneously. The results demonstrated that ectopically expressed IL-18 promoted cell motility in vitro and down-regulated E-cadherin expression of PLA801C transfectants, while IL-18 antisense remarkably decreased cell invasion potency in vitro and notably increased E-cadherin expression of PLA801D transfectants, indicating that IL-18 might play a role in metastasis by inhibiting E-cadherin expression.

Animals↗
PubMed2025

Colorectal Liver Metastasis Pathomics Model: Integrating Single-Cell and Spatial Transcriptome Analysis With Pathomics for Predicting Liver Metastasis in Colorectal Cancer.

The liver is the primary target organ for hematologic metastasis of colorectal cancer (CRC), and CRC liver metastasis (CRLM) often precludes radical resection, making it the leading cause of death in patients with CRC. To improve the identification and prediction of liver metastasis risk, we identified a cell type of liver metastasis--triggering malignant cells (LMTMCs) through integrating single-cell RNA sequencing and spatial transcriptome analysis. Multiomics cell communication analysis indicated that the interaction between fibroblasts and LMTMCs through the COL1A1-CD44/SDC4 and LAMA4-CD44 signaling axes could promote CRLM. By applying the one-class logistic regression algorithm, we developed a CRLM scoring system in the bulk RNA-sequencing data according to the abundance of LMTMCs in each individual. Using the grouping labels derived from the CRLM scoring system in the bulk data and the corresponding whole-slide images without any manual annotations at the region or pixel level, processed via slide-level weakly supervised learning, a deep-learning model based on the ResNet18 architecture, called Colorectal Liver Metastasis Pathomics Model, was developed to predict the risk of liver metastasis in patients with CRC. The Colorectal Liver Metastasis Pathomics Model achieved an area under the curve of 0.84 at the internal test set of The Cancer Genome Atlas-CRC histology images. In the external independent validation sets, namely the Affiliated Hospital of Southwest Medical University and the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University cohorts, the areas under the curve were 0.89 and 0.72, respectively, indicating effective classification performances. This study provided new insights and tools for the early identification of CRLM and demonstrated the potential of combining multiomics with deep learning-based pathomics in cancer research.

Humans↗
PubMed1988

Cervical lymph node metastasis in carcinoma of the tongue. Correlation between clinical and histopathological findings and metastasis.

The factors relating to lymph node metastasis occurring in association with carcinoma of the tongue have been investigated clinically and histopathologically by many authors. Nevertheless, accuracy in predicting lymph node metastasis has not yet been attained. The present study describes the results of analysis performed in an attempt to predict lymph node metastasis of carcinoma of the tongue. Ninety-eight patients with squamous cell carcinoma of the tongue who were treated at our institution were investigated. Among the 98 patients, lymph node metastases were histologically proven after neck dissection in 40 patients. For statistical analysis in the present study, the quantification theory Type II of Hayashi (1954) was employed for discriminatory analysis. According to this discriminatory analysis, the correlations between the clinical (age, tumour size, N-category) and histopathological (degree of keratinization, mitoses, structure, mode of invasion) findings and metastasis were assessed on the basis of the partial correlation coefficients; these coefficients for each finding were not greatly different from each other and 74 out of 98 patients (76%) could be differentiated between patients with metastasis and without metastasis accurately. The prediction of lymph node metastasis by such discriminatory analysis had significant validity.

Adult↗
PubMed1992

Should all the N3 lymph nodes group metastasis be regarded as distant metastasis (M1) in curatively resected gastric cancer?

Recently, metastasis to N3 lymph nodes group was regarded as distant metastasis by the new TNM staging system due to poor overall survival. However, the 5-year overall survival rate of patients with metastasis to N3 groups was 34.5% after curative surgery. Moreover, in patients with metastasis to lymph node subgroups of #12, #13, #14, the overall 5-year survival rate increased upto 47.2% after curative resection and adjuvant chemotherapy. This was similar to that of the patients with metastasis to N1 and N2 lymph nodes groups. But in these highly tumor burden states, no survival benefit was found with the addition of immunotherapy to chemotherapy as we achieved in stage II and III. Therefore, we suggest that, at least, metastasis to #12, #13, #14 lymph nodes subgroups should not be categorized as a distant metastasis. And in these situations, active curative radical surgery with extended lymphadenectomy and adjuvant chemotherapy are recommended.

Adult↗
PubMed1989

[Metastasis into the paracystium of urinary bladder carcinoma--the rate position and morphology of metastasis].

Twenty-three patients, who underwent radical cystectomy and pelvic lymph node dissection for bladder carcinoma from November 1985 to November 1987, were studied pathologically. We evaluated the rate, position and morphology of metastasis into the neurovascular corridor or paracystium. The stages of the twenty-three patients were G1 1, G2 10, G3 12 and pT1a 1, pT1b 4, pT2 8, pT3a 2, pT3b 7, pT4 1. Of the 23 specimens, 22 (95%) were found to contain metastasis in the connective tissue of the paracystium. Lymph node metastasis was recognized in four patients (17%). Metastasis in connective tissue around the iliac lymph node was recognized in 5 patients (22%). Of these 5 patients, 3 were free from lymph node metastasis. The morphological pattern of metastasis was ranged from a few tumor cells to massive tumor cells with proliferation of fibroblasts. The existence of metastasis in the paracystium should be evaluated morphologically for urinary bladder carcinoma.

Adult↗
PubMed2000

[Correlation between expression of metastasis-related genes and lymph node metastasis in testicular cancer].

To investigate the factors related to lymph node metastasis of testicular germ cell tumors, we first established a seminoma orthotopic model with lymph node metastasis in SCID mice by inoculating small fragments from subcutaneous xenografts. Second, we compared the expression patterns of metastasis-related genes of the seminoma xenografts and of the TCam-2 cells which were established as a seminoma cell line from a primary testicular seminoma. Third, we immunohistochemically analyzed human germ cell tumors (25 seminomas, 17 nonseminomas) using monoclonal antibodies to CD34, VEGF, VEGF-C, Flt-4, MMP-2 and E-cadherin. Testicular seminoma xenografts grew in 32/32 (100%) of the inoculated mice, of which 15 (47%) developed macroscopic metastasis to the renal hilar lymph node. Circulating tumor cells were detectable by using a PCR assay for the human beta-globin gene in 25/32 (78%) mice, although metastatic foci were not histologically evident in the visceral organs, including lungs, liver, kidneys and spleen. This may reflect the lymphophilic characteristics of the seminoma cells used. Regarding mRNA expression of metastasis-related genes, an increased expression of MMP-2 and VEGF compared with that in the s.c. xenografts was demonstrated by RT-PCR assay in the testicular seminoma xenografts. In addition, uPAR, MMP-1, MMP-2, MT1-MMP and MT3-MMP showed a a stronger expression and PAI-2 a weaker expression in the seminoma xenografts than did TCam-2 cells. These results suggest a higher metastatic potential of the seminoma xenografts, especially testicular xenografts, as compared with TCam-2 cells. In the immunohistochemical study, a significant correlation was found between MMP-2 expression and lymph node metastasis, which is compatible with the results for the metastasis-related gene expression from the seminoma xenografts.

Animals↗
PubMed2003

[Expression of the metastasis-associated gene 1 in laryngeal squamous cell carcinoma: correlation with cervical lymph node metastasis].

OBJECTIVE: The purpose of study was to examine the mRNA expression levels of the metastasis-associated gene1 (MTA1) in laryngeal squamous cell carcinoma (LSCC), so to evaluate its relationship with metastases. METHODS: Forty-eight surgically resected primary LSCC (16 supraglotti laryngeal carcinomas with cervical lymph node metastasis, 16 supraglotti laryngeal carcinomas with cervical lymph node-negative metastasis, 16 glottic carcinoma with cervical lymph node-negative metastasis) and 16 normal laryngeal mucosa was examined for mRNA expression of MTA1 by reverse transcription-polymerase chain reaction(RT-PCR). RESULTS: The frequency of MTA1 mRNA positive expression in 16 LSCC with cervical lymph node metastasis was 100%, but no expression of MTA1 mRNA was observed in other LSCC with cervical lymph node-negative metastasis (16 supraglotti laryngeal carcinomas and 16 glottic carcinoma) and 16 normal laryngeal mucosa. CONCLUSION: MTA1 gene is strongly related to cervical lymph node metastasis of LSCC, and may serve as a early diagnosis indicator.

Adult↗
PubMed1990

[A clinical study of 76 cases in carcinoma of the colon and rectum with metastasis to the peri-aortic lymph nodes. With particular reference to the skip metastasis in carcinoma of the sigmoid colon to the peri-aortic lymph nodes].

The therapeutic result by tumorous site were evaluated in 76 cases of carcinoma of the colon and rectum with the confirmed presence of metastasis to the peri-aortic lymph nodes. The results revealed that significant good out-comes were noted in the relatively non-curative cases of carcinoma of the sigmoid colon, with particularly good prognosis being found in six cases with skip metastasis. There was a 26.1% (6/23) incidence of the skip metastasis in carcinoma of the sigmoid colon with the peri-aortic lymph nodes metastasis. We confirmed two lymphatic routes of the skip metastasis; one route was from the lymph nodes near the tumor to the para-aortic lymph nodes directly, and the other was from the lymph nodes near the tumor to the lymph nodes at the aortic diffract directly and finally to the para-aortic lymph nodes. In the all six cases, the peri-aortic lymph nodes metastasis occurred only in inferior site of the inferior mesenteric artery. The average number of the peri-aortic lymph nodes metastasis were as few as 1.7 in these cases. The prognosis was favorable with three of the six cases scoring a three-year survival and included a five-year survival case.

Adult↗
PubMed1993

Bone metastasis as a prognostic factor in breast cancer patients with liver metastasis given OK-432-combined adoptive immunotherapy via the hepatic artery.

The outcome in 31 patients with liver metastases from breast cancer given OK-432-combined adoptive immunotherapy via the hepatic artery was analyzed. Patients received intraarterial OK-432, a streptococcal preparation, followed by the transfer of autologous lymphocytes cultured with autologous tumor extract and interleukin-2 for 9-13 days. Liver lesions were evaluable in 11 of the 12 patients with bone metastasis (group A) and in 16 of the 19 patients without bone metastasis (group B). Complete response (CR) in the liver was attained in 8 patients in group A, but in only 1 in group B (p < 0.01). In group A, radiological features of all metastatic foci of bone improved after CR in the liver. Moreover, the median survival time (MST) of group A (20 months) was longer (p = 0.06) than that of group B patients with extra-hepatic metastasis (n = 12; MST = 6 months), while group B patients with liver metastasis alone (n = 7) showed a MST similar to that of group A. Thus, loco-regional immunotherapy via the hepatic artery was found to be useful in controlling both liver and bone metastasis from breast cancer. Moreover, in breast cancer patients with liver metastasis, bone metastasis appears to be a prognostic factor associated with good response to this immunotherapy.

Adult↗
PubMedDate not supplied

Suppression of human ovarian carcinoma metastasis by the metastasis-suppressor gene, BRMS1.

Metastasis-suppressor genes, by definition, suppress metastasis without affecting tumorigenicity and, hence, present attractive targets as prognostic or therapeutic markers. BRMS1 (breast cancer metastasis suppressor) has recently been identified as a metastasis-suppressor gene for human breast cancer and melanoma. Expression of BRMS1 messenger RNA (mRNA) in multitissue including normal prostate, ovarian, testis, and colon has been detected by northern blot analysis. We hypothesize that the role of BRMS1 in tumor progression may not be limited to breast cancer and melanoma. We previously found that BRMS1 mRNA levels in primary ovarian epithelial carcinomas were significantly lower than that in normal ovarian and benign tumors (P < 0.05), and statistical analysis of BRMS1 mRNA levels revealed that BRMS1 mRNA levels were significantly higher in early tumor stages (I, II) compared with advanced tumor stages (III, IV) in which lymph node or distant metastases were present (P < 0.01). Our data showed that reduced BRMS1 mRNA seems to influence ovarian carcinoma metastatic ability. Therefore, we transfected BRMS1 plasmid into highly malignant ovarian carcinoma cell line, HO-8910PM, and examined cell biologic behaviors including proliferation, adhesion, invasion, and metastasis in vitro and in vivo. BRMS1 expression did not alter the proliferation of HO-8910PM cells in vitro and primary tumor formation in vivo. But, BRMS1 expression significantly suppressed the cell adhesion to extracellular matrix components and in vitro cell invasion in BRMS1-transfected HO-8910PM cells compared to parental HO-8910PM and vector-only transfectants (HO-8910PM-vect). Furthermore, motility of BRMS1 transfectants was inhibited. lung colony formation of intravenously injected BRMS1 transfectants in nude mice was significantly reduced. Also, BRMS1 transfectants form significantly less metastatic to organs of peritoneal cavity in orthotopically implanted ovarian tumor nude models. We further discovered that BRMS1 expression did downregulate expression of an actin-bundling protein associated with cell motility -fascin, which perhaps is the mechanism underlying BRMS1 suppression of metastasis. These data suggested that in addition to its already described role in breast cancer and melanoma, BRMS1 functions as a metastasis-suppressor gene in ovarian carcinoma by modifying several metastatic-associated phenotypes, offering a new target for therapeutic intervention.

Animals↗
PubMedDate not supplied

Lymph node metastasis in squamous cell carcinoma of the oral cavity: correlation between histologic features and the prevalence of metastasis.

A retrospective study was made of the correlation between preoperative clinical or histologic findings and the prevalence of lymph node metastasis in 60 patients with squamous cell carcinoma of the oral cavity who had histologically confirmed neck metastasis. Of these 60 patients, 39 with clinically N+ necks underwent immediate therapeutic neck dissection, and 21 whose necks were initially N0 but progressed to N+ during observation underwent subsequent therapeutic neck dissection. The primary site, TNM staging, histologic grade of malignancy of biopsy specimen, and location and number of histologically positive lymph nodes were reviewed in each case. The results were as follows: (1) The prevalence of neck metastasis was not significantly correlated with primary site and T stage; however, there was an apparent correlation between histologic grade of malignancy and the prevalence of neck metastasis. Patients with grade I-II histologic malignancy showed limited metastases that involved lymph nodes in levels I-II. On the other hand, patients showing grade III-IV histologic malignancy often had metastases that extended beyond level III, regardless of T stage. These results suggest that histologic grade of malignancy, as well as clinical features, must be taken into consideration when deciding whether supraomohyoid neck dissection is indicated. (2) The group that underwent subsequent neck dissection exhibited less advanced neck metastasis and a better prognosis than the group which underwent immediate neck dissection. These findings show that if they are closely followed up, it is possible to delay neck dissection in N0 patients until a neck metastasis is detected.

Adult↗
PubMed1984

Temperature-dependent metastasis of the Lucke renal carcinoma and its significance for studies on mechanisms of metastasis.

Metastasis is temperature dependent in the renal adenocarcinoma of the North American leopard frog, Rana pipiens. Widespread, multiple, metastatic colonies occur in tumor-bearing frogs kept at 28 degrees C for 50 days while tumor-bearing frogs kept at 7 degrees C for 98 days or more have either no secondary deposits or they have only an occasional small metastatic nodule. An attractive aspect of the frog tumor is that invasion and metastasis can be permitted or inhibited by the manipulation of temperature alone-no exogenous chemicals or drugs are required for the effect. Because of this, biological variables which reproducibly and specifically associate with metastasis permissive conditions when ambient temperature is cycled between permissive and inhibitory values are strong candidates for being causal elements in the multistep process leading to metastasis. Intravascularly injected labelled renal tumor cells reached all organs studied in as little as 15 minutes at both metastasis restrictive and permissive temperature. The results with tumor cell inoculation dispose of the possibility that failure of metastasis in chilled animals is due to cold-induced changes in blood flow. Histologically typical metastatic colonies developed in frogs, kept at the permissive temperature, after injection with disaggregated tumor cells which were previously cryopreserved. Frog tumors elaborate type I collagenase in a temperature dependent manner. Type IV collagenase has been demonstrated as well. Tumor cell detachment in vitro, assembly and disassembly of tumor cell cytoplasmic microtubules, and invasion in vitro, are all temperature dependent.

Animals↗
PubMed2000

Intravascular origin of metastasis from the proliferation of endothelium-attached tumor cells: a new model for metastasis.

Metastasis is a frequent complication of cancer, yet the process through which circulating tumor cells form distant colonies is poorly understood. We have been able to observe the steps in early hematogenous metastasis by epifluorescence microscopy of tumor cells expressing green fluorescent protein in subpleural microvessels in intact, perfused mouse and rat lungs. Metastatic tumor cells attached to the endothelia of pulmonary pre-capillary arterioles and capillaries. Extravasation of tumor cells was rare, and it seemed that the transmigrated cells were cleared quickly by the lung, leaving only the endothelium-attached cells as the seeds of secondary tumors. Early colonies were entirely within the blood vessels. Although most models of metastasis include an extravasation step early in the process, here we show that in the lung, metastasis is initiated by attachment of tumor cells to the vascular endothelium and that hematogenous metastasis originates from the proliferation of attached intravascular tumor cells rather than from extravasated ones. Intravascular metastasis formation would make early colonies especially vulnerable to intravascular drugs, and this possibility has potential for the prevention of tumor cell attachment to the endothelium.

Animals↗