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PubMed1983

Lymphatic metastasis.

Lymphatic metastasis is an important mechanism in the spread of human cancer. During its course, tumor cells first penetrate the basement of membrane of the epithelium, in which they arise, and then the underlying connective tissue, carried partly by hydrostatic pressure. They enter the lymphatic partly by active movement, pass up the lymphatic trunk; they then settle and proliferate in the subcapsular sinus, penetrate its endothelium and proliferate and destroy the node. There are varied forms of immune response in the node and in human nodes often a complex fibrous and vascular response. The degree of lymphocytic response may be important for prognosis. The nodal reaction may be stimulated by release of antigens from the tumor. One of the most studied animal models of lymphatic metastasis is that which occurs in the politeal node after injection of tumor into the footpad. This model has been used to show that tumor cells enter lymphatics through gaps in endothelium, probably between endothelial cells, and that lymph nodes can destroy small numbers of tumor cells. Local immunotherapy and chemotherapy can sterilize a lymph node of tumor cells; the modes of treatment used have included intralymphatic injection and encapsulation of chemotherapeutic agents in liposomes. Prior radiotherapy may accelerate metastasis possibly by making tumor cells shed into lymphatic vessels. Lymph nodes are rather poor barriers to tumor cells. The prognostic significance of lymph node metastasis varies within tumor type; if hematogenous metastasis is early, then the presence of lymph node metastasis is of lesser prognostic significance. Lymph nodes can probably destroy only small numbers of tumor cells. Tumor cell heterogeneity is of importance in many aspects of metastasis; while clonal variation may be of importance in determining lymph node metastasis, it is not yet clear how important this is, nor whether specific clones metastasize specifically to lymph nodes. Lymphography is well established in diagnosis of lymphatic metastasis. A recent interesting development has been to inject antibodies labeled with a radioactive label, and image the label in lymph nodes with a gamma-camera. If anti-tumor antibodies are used in this way it may be possible to detect lymph node metastasis. Within the expanding field of tumor metastasis, lymphatic metastasis needs much more attention, particularly in relation to the diagnosis and treatment of the lymphatic spread of human cancer.

Animals↗
PubMed1998

[Locally advanced prostate carcinoma (T2b-T4 N0) without and with clinical evidence of local progression (Tx N+) with lymphatic metastasis. Is radiotherapy for pelvic lymphatic metastasis indicated or not?].

BACKGROUND: There is a greater controversy regarding the indication of radiotherapy of the pelvic lymphatics in patients with suspected lymph node metastases in locally advanced prostate cancer (T2b-4 N0) on the one hand and in patients with pathologically proven lymph node metastases in locoregional advanced prostate cancer (Tx pN+) on the other hand following definitive radiotherapy and radical prostatectomy. This paper investigates the possible indications for radiotherapy of the pelvic lymphatics in the light of data from the literature. PATIENTS AND METHODS: Because data from several retrospective studies concerning radiotherapy of the pelvic lymphatics indicated a better outcome, the RTOG conducted 2 prospective randomised studies (RTOG 75-06, 77-06) to address these questions. However, the results of these studies showed no better survival or cause specific survival for patients treated for the paraaortal or pelvic lymphatics and therefore, radiotherapy of the pelvic lymphatics was no more advocated. A reanalysis showed several problems of the study design and it was concluded that the studies couldn't prove the question of elective radiotherapy of the pelvic lymphatics. In RTOG 77-06 patients with T1b/T2 tumors were investigated. Therefore, there is no prospective study investigating the elective radiotherapy in patients with T3-tumors, who are at high risk of pelvic lymph node metastases. RESULTS: Today there is no indication for treating the paraaortal lymphatics in patients with locoregional advanced prostate cancer. Many radiotherapists perform the elective radiotherapy of pelvic lymphatics when the risk of metastases is above 15 to 20% because retrospective data indicate a better outcome. On the other hand, many others don't treat them because RTOG 75-06 and 77-06 didn't demonstrate a better outcome. Laparoscopic lymphadenectomy with low morbidity seems to be helpful as in pN0 patients radiotherapy is not necessary. Where performing laparoscopic pelvine lymphadenectomy is impossible the probability of the frequency of lymph node metastases can be estimated using the clinical tumor stage, the Gleason-score and the pretherapeutic PSA. In case of proven metastases (pN+) some retrospective data indicate that patients with micrometastasis could profit from aggressive treatment. In case of proven metastases and extirpation by lymphadenectomy it seems that patients with hormonal therapy and radiotherapy have a longer tumor-free interval. However, there are no data from randomized trials. CONCLUSIONS: Every radiotherapist has to make his own decision for radiotherapy of the pelvic lymphatics as there is no standard treatment. Two randomised studies are open and recruiting patients. These are one study of the ARO, investigating patients with histologically proven lymph node metastases and one study of the RTOG (RTOG 9413), investigating patients with an estimated risk of lymph node metastases > 15%. In case of radiotherapy of the pelvic lymphatics a dose of 45 Gy for suspected metastases and 50.4 Gy for proven metastases is recommended.

Carcinoma↗
PubMed1980

Lymphatic metastasis: invasion of lymphatic vessels and efflux of tumour cells in the afferent popliteal lymph as seen in the Walker rat carcinoma.

When twenty million Walker rat carcinoma cells are injected into the footpad of albino outbred rats, there is progressive metastasis to the draining popliteal and thence para-aortic lymph nodes. The lymphatic duct efferent from the footpad and afferent to the popliteal node has been cannulated; it has been shown that there is a continuous and progressively increasing output of tumour cells, small and large lymphocytes, macrophages and polymorphs from the footpad. About 20 per cent of the cells are tumour cells. The number of tumour cells in the popliteal and para-aortic nodes has been counted using a Coulter counter and subsequent differential counting of stained smears; the nodes contain a progressively increasing number of both tumour cells and lymphoreticular cells. The early accumulation of tumour cells in the para-aortic nodes makes it evident that tumour cells pass rapidly through the primary node. Examination of the simulated primary tumour by transmission electron microscopy suggests that tumour cells move actively toward lymphatics and protrude cytoplasmic processes through gaps in the endothelium. The endothelial cell then degenerates in close proximity to tumour cell processes. This leaves gaps through which tumour cells may pass and ultimately results in lymphatics with large defects in their walls.

Animals↗
PubMed2002

Lymphatic metastasis in the absence of functional intratumor lymphatics.

Lymphatic metastasis contributes to mortality from solid tumors. Whether metastasizing cancer cells reach lymph nodes via intratumor lymphatic vessels is unknown. Here, we examine functional lymphatics associated with mouse tumors expressing normal or elevated levels of vascular endothelial growth factor-C (VEGF-C), a molecule that stimulates lymphangiogenesis. Although VEGF-C overexpression increased lymphatic surface area in the tumor margin and lymphatic metastasis, these tumors contained no functional lymphatics, as assessed by four independent functional assays and immunohistochemical staining. These findings suggest that the functional lymphatics in the tumor margin alone are sufficient for lymphatic metastasis and should be targeted therapeutically.

Adenocarcinoma↗
PubMed1986

[Indication of extended radical operation for gastric antrum cancer assessed by rules of lymphatic metastasis].

Study on the lymphatic metastasis rule of 83 cases of gastric antrum carcinoma showed overall lymphatic metastasis rate (LMR) was 80.7% (67/83) and overall metastasis degree was 22.9% (i. e. 440 positive in the 1926 lymph nodes). There is no significant difference (P greater than 0.05) in LMR in the second line (N2) for the lesions with various biological features. Growth mode and histological type have the greatest influence on LMR in the third line (N3). N3 in the infiltration type and poorly or undifferentiated type is obviously higher than that in the localized and well-differentiated types (P less than 0.01). In view of the results, we conclude that extended radical operation (R3) should not be used as a routine operation for gastric cancer and be selectively carried out referring to the biological features of the tumor. In general, stage I gastric cancer is not indicated for R3; stages II and III are absolute indications; stage IV is the relative indication, i. e. group T1-4a N3M0 can be indicated; a part of T4b can also be treated by R3 resecting en bloc the involved organs but group M1 would miss the radical treatment. Besides, total gastrectomy or combined resection of spleen, body and tail of the pancreas should not be done routinely for gastric antrum cancer. They are to be performed according to the degree of involvement of the gastric body and metastasis in the lymph node groups 1, 2 and 3, 4.

Female↗
PubMed1983

Experimental lymphatic metastasis.

A model of lymphatic metastasis of cancer has been established by injecting tumour cells into the rat footpad and examining the draining popliteal lymph node. The node can probably destroy only a few tumour cells; thereafter metastasis is progressive and lethal. The tumour cells penetrate the lymphatic endothelium, in the footpad either by moving singly between intact endothelial cells, by destroying the endothelium, or by passing in clumps between the endothelial cells. Tumour cells may then be obtained from the lymph by cannulation of the lymphatic trunk. These experiments pose the question: is local lymphatic chemotherapy useful in treating lymphatic metastasis?

Animals↗
PubMed2004

Construction and selection of subtracted cDNA library of mouse hepatocarcinoma cell lines with different lymphatic metastasis potential.

AIM: In order to elucidate the molecular mechanism of lymphatic metastasis of hepatocarcinoma, we detected the difference of gene expression between mouse hepatocarcinoma cell lines Hca-F and Hca-P with different lymphatic metastasis potential. METHODS: cDNA of Hca-F cells was used as a tester and cDNA of Hca-P cells was used as a driver. cDNAs highly expressed in Hca-F cells were isolated by the suppression subtractive hybridization (SSH) method. The isolated cDNA was cloned into T/A cloning vector. The ligation products were transformed into DH5alpha competent cells. Individual clones were randomly selected and used for PCR amplification. Vector DNA from positive clones was isolated for sequencing. RESULTS: There were 800 positive clones in amplified subtracted cDNA library. Random analysis of 160 clones with PCR showed that 95% of the clones contained 100-700 bp inserts. Analysis of 20 sequenced cDNA clones randomly picked from the SSH library revealed 4 known genes (mouse heat shock protein 84 ku, DNA helicase, ribosomal protein S13, ethanol induced 6 gene) and 3 expressed sequence tags (ESTs). Four cDNAs showed no homology and presumably represent novel genes. CONCLUSION: A subtracted cDNA library of differentially expressed genes in mouse heptocarcinoma cell lines with different lymphatic metastasis potential was successfully constructed with SSH and T/A cloning techniques. The library is efficient and lays a solid foundation for searching new lymphatic metastasis related genes. The expression of mouse heat shock protein gene, DNA helicase and other 4 novel gene may be different between mouse heptocarcinoma cell lines with different lymphatic metastasis potential.

Animals↗
PubMed2005

Vascular endothelial growth factor-a promotes peritumoral lymphangiogenesis and lymphatic metastasis.

Metastases are commonly found in the lymphatic system. The molecular mechanism of lymphatic metastasis is, however, poorly understood. Here we report that vascular endothelial growth factor (VEGF)-A stimulated lymphangiogenesis in vivo and that overexpression of VEGF-A in murine T241 fibrosarcomas induced the growth of peritumoral lymphatic vessels, which occasionally penetrated into the tumor tissue. As a result of peritumoral lymphangiogenesis, metastases in lymph nodes of mice were detected. VEGF-A-overexpressing tumors contained high numbers of infiltrating inflammatory cells such as macrophages, which are known to express VEGF receptor (VEGFR)-1. It seemed that in the mouse cornea, VEGF-A stimulated lymphangiogenesis through a VEGF-C/-D/VEGFR-3-independent pathway as a VEGFR-3 antagonist selectively inhibited VEGF-C-induced, but not VEGF-A-induced, lymphangiogenesis. Our data show that VEGF-A contributes to lymphatic mestastasis. Thus, blockage of VEGF-A-induced lymphangiogenesis may provide a novel approach for prevention and treatment of lymphatic metastasis.

Animals↗
PubMed2006

[Correlation of cervical lymphatic metastasis to prognosis of T3-T4 glottic cancer].

BACKGROUND & OBJECTIVE: The cervical lymphatic metastasis rate of glottic cancer is low, and has seldom been reported. This study was to explore the factors related to cervical lymphatic metastasis of T3-T4 glottic cancer, and analyze its correlation to prognosis. METHODS: Clinical data of 83 patients with T3-T4 glottic cancer, treated in Cancer Center of Sun Yat-sen University from 1992 to 2000, were reviewed retrospectively. The lymphatic metastasis rate, distribution of metastatic lymph nodes, influence factors of neck recurrence of cN0 glottic cancer, and correlation of cervical lymphatic metastasis to prognosis of T3-T4 glottic cancer were analyzed. RESULTS: Overall lymphatic metastasis rate was 20.5%. The neck recurrence rate of cN0 patients was 14.3%. Most metastatic lymph nodes located at the ipsilateral levels II, III, and IV, while only 1 located at the contralateral level II. For cN0 patients, there was no difference in the neck recurrence rate between observation group and prophylactic cervical radiation group (P=0.772). Histopathologic differentiation affected the neck recurrence of cN0 patients (P=0.028); while T stage did not relate to the neck recurrence (P=0.217). The prognosis of cN+ patients was poorer than that of cN0 patients (P<0.001). The neck recurrence of CN0 patients did not affect the prognosis (P=0.460). CONCLUSION: Most metastatic lymph nodes of T3-T4 glottic cancer locate at the ipsilateral levels II, III, and IV. Poor differentiation is significantly correlated to high risk of neck recurrence among cN0 patients. However, the recurrence does not affect the prognosis. Close observation should be done to the cervix of cN0 patients; while neck dissection should be done to cN+ patients.

Adult↗
PubMed2006

[Relevant factors of lymphatic metastasis in rectal carcinoma].

OBJECTIVE: To investigate the rules of lymphatic metastasis of rectal carcinoma, and to help clinical diagnosis and treatment. METHODS: A retrospective analysis was performed in the 979 patients with rectal carcinoma who underwent surgical resection from 1995 to 2004. The associations between lymphatic metastasis and clinicopathologic variables were evaluated by Chi-squared test and logistic regression. RESULTS: The rate of lymph node metstasis was 71.4% for patients younger than 30 years old, 40.7% in the patients with tumor diameters over 6 centimeters, 82.5% in the patients with extraneous tumor invasion, 71.6% for patients of poor-differentiated adenocarcinoma, 70.4% for patients with mucoid adenocarcinoma, 100% for patients with signet-ring cell carcinoma and 46.4% for patients with more than half intestinal circumference invasion. Logistic regression analysis showed that the degree of lymphatic metastasis was related to the differentiating degrees, depths of tumor invasion and intestinal circumference invasion, and the differentiating degree was the major factor. CONCLUSION: The lymphatic metastasis of rectal carcinoma is related to age, tumor size, intestinal circumference invasion, depth of tumor invasion and the differentiating degree of the tumor; the differentiating degree is the major factor.

Adenocarcinoma↗
PubMedDate not supplied

Tumor cell adhesion to frozen lymph node sections--an in vitro correlate of lymphatic metastasis.

Two variant sublines of the murine 3LL carcinoma with divergent potentials for lymphatic metastasis were used to assess the relationship between tumor cell potential for lymphatic metastasis and its ability to adhere specifically to lymphatic tissue. Using fresh cryostat sections of lymph nodes and spleens, it was found that tumor cell adhesion to the lymphatic tissue but not to control sections of the brain correlated well with their ability to metastasize lymphatically. On the other hand, there was no correlation between tumor cell attachment to isolated lymphocytes in vitro and their potential for lymphatic metastasis. When tumor cells were pretreated enzymatically or with the metabolic inhibitor tunicamycin with the aim of modulating cell surface carbohydrates, adhesion to the lymph node sections could be significantly reduced, implicating cell surface glycoproteins and in particular galactosyl groups in the binding. The results suggest that tumor cell attachment to lymph node cryostat sections could provide a useful tool in the study of host-tumor interactions in lymphatic metastasis.

Animals↗
PubMed2006

[Lymphatic metastasis intensity of and lymphadenectomy for thoracic esophageal squamous cell carcinoma].

BACKGROUND & OBJECTIVE: The intensity of lymphatic metastasis consists of lymph node metastasis number (LMN) and lymph node metastasis ratio (LMR). LMR is the ratio of positive nodes to dissected nodes. LMN and LMR are 2 important prognostic factors of esophageal cancer, and are adopted in tumor staging. This study was to assess the lymphatic metastasis intensity of thoracic esophageal squamous cell carcinoma (ESCC), and explore the influential factors and lymphadenectomy pattern. METHODS: A total of 120 patients with ESCC had been operated in the Second Affiliated Hospital of Sun Yat-sen University from 1998 to 2000. The lymph nodes were dissected according to the mapping scheme of the American Thoracic Society (ATS) modified by Casson et al. RESULTS: A total of 2 631 lymph nodes were dissected with an average of 22 lymph nodes in each case. The cervical LMR was significantly higher in the upper thoracic ESCC than in the middle and lower thoracic ESCC (20.9% vs. 12.9% and 6.8%, P<0.05). The left gastric LMR was significantly higher in the lower thoracic ESCC than in the middle and upper thoracic ESCC (37.5% vs. 17.5% and 7.1%, P<0.05). Subcarinal metastatic lymph nodes were often found in the middle thoracic ESCC. T stage, histological differentiation, and circum wall involvement degree were correlated to lymphatic metastasis intensity (P<0.05); the length of esophageal lesion had no correlation to lymphatic metastasis intensity (P>0.05). The survival time of the patients received the right thoracic esophagectomy with 3-field lymphadenectomy (3-FL) was significantly longer than that of the patients received the left thoracic esophagectomy with 2-FL (P<0.05). CONCLUSIONS: During the operation on ESCC, the regions with high lymphatic metastasis intensity should be dissected. T stage, histological differentiation, and circum wall involvement degree are important influential factors of lymphatic metastasis intensity. The right thoracic esophagectomy with 3-FL is superior to the left thoracic esophagectomy with 2-FL.

Adult↗
PubMed1996

Inhibition of lymphatic metastasis in a syngeneic rat fibrosarcoma model by an angiogenesis inhibitor, AGM-1470.

We examined whether lymphatic metastasis was inhibited by the potent angiogenesis inhibitor AGM-1470 [O-(chloroacetyl-carbamoyl)fumagillol, TNP-470] using a rat lymphatic metastasis model. Clone A of the rat fibrosarcoma AS653HM, when inoculated into the footpads of syngeneic rats, highly and preferentially metastasized to lymph nodes. In contrast, when AGM-1470 was administered subcutaneously to rats bearing the tumor cells, the tumor growth and incidence of metastasis in the lymph nodes were reduced in a dose- and schedule-dependent manner. Similar inhibition of lymphatic metastasis was also observed in the rats in which treatment with AGM-1470 was initiated following resection of the primary tumor in the foot, indicating that the treatment with AGM-1470 inhibited the progression of lymphatic metastasis at the metastatic sites of the lymph nodes. These results suggest that AGM-1470 can be a potential agent to prevent lymphatic metastasis.

Animals↗
PubMed1988

Involvement of soybean agglutinin binding cells in the lymphatic metastasis of the R3230AC rat mammary adenocarcinoma.

Many human tumors, such as those of the breast, metastasize initially via the lymphatics. The tumor cell surface is believed to play a critical role in this process. To study the cell surface properties involved in dissemination, the poorly metastasizing R3230AC rat mammary adenocarcinoma was enriched for metastasizing cells by excising rare lymph node metastases arising after the s.c. injection of 10(6) cells and reinjecting these cells into another series of rats. By repeated enrichment cycles, the frequency of lymphatic metastasis was increased from 10 to 60-100% of the animals given injections. Fluorescein-conjugated lectins were used to probe the tumor cell surface. It was found that the percentage of cells in the population able to bind high levels of the lectin, soybean agglutinin (SBA), increased from 11 to almost 80% in the highly metastatic, enriched cell populations. A linear correlation (r = 0.92; P less than 0.001) was found between the percentage of cells in the population which bound high levels of SBA and the frequency of lymphatic metastasis in a series of enriched cell lines. Clones which bound high levels of SBA metastasized to lymph nodes at a high frequency, while clones which bound only low amounts of SBA exhibited a low frequency of lymphatic metastasis regardless of the metastatic potential of the cell line from which the clones were isolated. The binding of SBA to the cell was reduced by preincubation of the lectin with galactose, completely blocked by incubation with N-acetylgalactosamine, and unaffected by incubation with glucose or mannose, demonstrating that SBA was recognizing a N-acetylgalactosamine-containing component of the cell surface. Cells enriched for lymphatic metastasis were not similarly enriched for hematogenous metastasis. While cell lines enriched for lymphatic metastasis have been previously described, this is the first report of a specific cell surface property, SBA-binding, associated with lymphatic metastasis.

Adenocarcinoma↗
PubMed2006

[The relationship between lymphangiogenesis and lymphatic metastasis in murine hepatic carcinoma of high and low metastatic potentialities].

OBJECTIVES: To study the relationship between lymphangiogenesis and lymphatic metastasis in mice bearing hepatic carcinoma and analyze the mechanism of the lymphatic metastasis. METHODS: Hepatic carcinoma cell lines of high and low potentialities of lymphatic metastasis were injected into the footpads of Balb/c mice. Their metastases to lymph nodes were examined. The tumor tissues of each group were stained with 5'-nucleotidase-ALP to observe the lymphoangiogenesis. The total RNA of high and low metastatic potential cell lines were extracted for metastasis gene DNA array. The vascular endothelial cell growth factor C (VEGF-C) and VEGF-D of each cell line were detected using semi-quantitative RT-PCR and were further quantatively analyzed using real time PCR. RESULTS: The para-common iliac a. and renal hilar lymph nodes metastases of the high metastatic potential cells were significantly higher than in the controls (P>0.05). The quantity of lymphatic vessels in the high metastasis group was significantly larger than that of the control group (P<0.05). The expressions of CD44, E-cadherin, HER2/neu, H-Ras and VEGF-C in the high metastasis group were higher than those in the low metastasis group shown by the cDNA micro array experiment but the expressions of nm23A, nm23-E4, p16ink4a, CD61 were lower. The VEGF-C expression was higher and the VEGF-D was lower in the high metastasis group compared to those of the low metastasis group shown by semi-quantitative RT-PCR. The secretion of VEGF-D was significantly lower and the ratio of VEGF-C/VEGF-D was significantly higher in the high metastasis group than the low metastasis group (P<0.05). CONCLUSIONS: The lymphatic metastasis of hepatic carcinoma is related to lymphoangiogenesis. The changes of VEGF-C and VEGF-D expressions might be a cause influencing the lymphoangiogenesis. VEGF-C/VEGF-D might be an effective parameter in affecting lymphatic metastases.

Animals↗
PubMed2003

[Study on the relationship between angiogenesis and cervical lymphatic metastasis in head and neck squamous cell carcinomas].

OBJECTIVE: To investigate the relationship between tumor angiogenesis and cervical lymphatic metastasis and the expression of vascular endothelial growth factor in head and neck squamous cell carcinomas. METHOD: Fifty-eight head and neck carcinoma tissue slides were immunohistochemically stained for anti-CD34 monoclonal antibody and anti-VEGF polyclonal antibody by SABC method. The intratumor microvessel density (IMVD) and the expression of vascular endothelial growth factor were measured. RESULT: 1. The mean IMVD with cervical lymphatic metastasis was significantly higher than those without cervical lymphatic metastasis in head and neck squamous cell carcinomas(27.92 +/- 9.11 and 20.69 +/- 7.08, P < 0.01); 2. The expression of vascular endothelial growth factor had a positive correlation with IMVD in head and neck carcinoma tissues (rs = 0.487, P < 0.01). CONCLUSION: IMVD may be an important predictor to cervical lymphatic metastasis in head and neck squamous cell carcinomas. Vascular endothelial growth factor may stimulate tumor angiogenesis in head and neck squamous cell carcinomas.

Adult↗
PubMed1987

Lymphatic metastasis and its treatment.

The treatment of lymphatic metastasis depends on an understanding of its basic biology. We are still uncertain as to how human cancer cells enter lymphatic vessels and as to what reactions if any in the draining lymph node inhibit metastasis. We are uncertain as to whether lymphatic metastasis is an indicator or a governor of rapid dissemination, and poor prognosis. We are uncertain as to whether it is worth attempting to treat lymphatic metastases by means supplementary to those used in treating systemic tumour dissemination. It may be possible to obtain local cure of a local lesion by local lymphatic therapy and to concentrate therapy locally by intralymphatic infusion of a chemotherapeutic agent or encapsulation in liposomes. This is at best accessory to obtaining systemic cure of systemically disseminated neoplasm. Optimal results could be expected from appropriate combinations of local and systemic immunotherapy, chemotherapy and radiotherapy, after appropriate surgical reduction in tumour bulk.

Combined Modality Therapy↗
PubMed2006

Role of the integrin-binding protein osteopontin in lymphatic metastasis of breast cancer.

Although a primary route of breast cancer metastasis is believed to be via lymphatics, the molecular factors involved are poorly understood. We hypothesized that one such factor may be the integrin-binding protein osteopontin (OPN), and we investigated this clinically and experimentally. In breast cancer patients undergoing sentinel lymph node biopsy, OPN levels were significantly higher in lymph node metastases than in the primary tumor (P < 0.001). To test the functional contribution of OPN to lymphatic metastasis and to determine whether the RGD (Arg-Gly-Asp) integrin-binding sequence of OPN is important for this process, we transfected wild-type OPN or mutant OPN (lacking the RGD sequence) into MDA-MB-468 human breast cancer cells. In vitro, cells overexpressing OPN demonstrated increased anchorage-independent growth in soft agar (P = 0.001) and increased RGD-dependent adhesion (P = 0.045). Following mammary fat pad injection of nude mice, cells overexpressing OPN showed increased lymphovascular invasion, lymph node metastases, and lung micrometastases at earlier time points (P = 0.024). Loss of the RGD region partially abrogated this effect in the lymphatics (P = 0.038). These novel findings indicate that OPN is a key molecular player involved in lymphatic metastasis of breast cancer, potentially by affecting RGD-mediated adhesive interactions and by enhancing the establishment/persistence of tumor cells in the lymphatics.

Adult↗