TMEM ACTIVE TEST AND USES THEREOF IN DIAGNOSIS, PROGNOSIS AND TREATMENT OF TUMORS
Disclosed are kits and methods for detecting the presence of tumor sites that are active in tumor cell dissemination and uses thereof for determining the risk of tumor cells undergoing hematogenous metastasis, for assessing the prognosis of a subject undergoing treatment for a localized tumor, for determining a course of treatment for a localized tumor, and for identifying agents to treat or prevent hematogenous metastasis.
1 . A method of determining the presence of one or more sites that are active in tumor cell dissemination in a subject, the method comprising
treating a tumor sample from the subject to detect Tie2, VEGFA, CD68, CD31, and VE-Cadherin and/or ZO-1, wherein the presence of CD68 indicates the presence of a macrophage and wherein the presence of CD31 indicates the presence of an endothelial cell, and
analyzing levels of Tie2, VEGFA, and VE-Cadherin and/or ZO-1,
wherein Tie2 Hi /VEGFA Hi peri-vascular macrophages associated with low levels of VE-Cadherin and/or ZO-1 endothelial staining indicate the presence of sites that are active in tumor cell dissemination (TMEM Active sites), and
wherein Tie2 Hi /VEGFA Hi peri-vascular macrophages associated with high levels of VE-Cadherin and/or ZO-1 endothelial staining indicate that TMEM sites are inactive in tumor cell dissemination.
2 . A method for determining the risk of tumor cells undergoing hematogenous metastasis comprising assaying a tumor sample from a subject for the presence of TMEM Active sites by the method according to claim 1 , wherein the risk of tumor cells undergoing hematogenous metastasis increases with the presence of TMEM Active sites.
3 . A method for determining a course of treatment for a tumor in a subject comprising assaying a tumor sample from the subject for the presence of TMEM Active sites by the method according to claim 1 , wherein the presence of TMEM Active sites indicates that the subject should be treated for a metastatic tumor or wherein a lack of TMEM Active sites indicates that the subject does not need to be treated for a metastatic tumor.
4 . A method for assessing the efficacy of an anti-cancer therapy in inhibiting tumor cell dissemination and metastasis in a subject comprising assaying a tumor sample from the subject for the presence of TMEM Active sites by the method according to claim 1 , wherein a reduction of TMEM Active sites in the subject undergoing anti-cancer therapy indicates that the anti-cancer therapy is effective and wherein a lack of reduction of TMEM Active sites in the subject undergoing anti-cancer therapy indicates that the anti-cancer therapy may not be effective.
5 . The method of claim 4 , wherein the anti-cancer therapy comprises administration to the subject of a drug that inhibits TMEM function.
6 . The method of claim 4 , wherein the anti-cancer therapy comprises administration of a Tie2 kinase inhibitor to the subject.
7 . A method of preventing or reducing tumor cell dissemination and metastasis in a subject comprising:
a) receiving an identification of the subject as having tumor sites that are active in tumor cell dissemination by the method according to claim 1 ; and
b) administering an anti-cancer therapy to the subject identified as having tumor sites that are active in tumor cell dissemination.
8 . The method of claim 7 , wherein the anti-cancer therapy comprises administration to the subject of a drug that inhibits TMEM function.
9 . The method of claim 7 , wherein the anti-cancer therapy comprises administration of a Tie2 kinase inhibitor to the subject.
10 . A method for identifying an agent to treat or prevent hematogenous metastasis, the method comprising contacting a tumor sample with the agent, assaying the tumor sample for the presence of TMEM Active sites by the method according to claim 1 , and analyzing whether or not the agent reduces the number of TMEM Active sites, wherein an agent that reduces the number of TMEM Active sites is a candidate agent for treating or preventing hematogenous metastasis.
11 . The method of claim 1 , wherein the tumor is a breast, pancreas, prostate, colon, brain, liver, lung, head or neck tumor.
12 . The method of claim 11 , wherein the tumor is a breast tumor.
13 . A kit for detecting the presence of tumor sites that are active in tumor cell dissemination, the kit comprising reagents to detect one or more of Tie2, VEGFA, CD68, CD31, and VE-Cadherin and/or ZO-1.
14 . The kit of claim 13 , further comprising instructions for a procedure to detect the presence of tumor sites that are active in tumor cell dissemination.
15 . The kit of claim 13 , wherein the tumor is a breast, pancreas, prostate, colon, brain, liver, lung, head or neck tumor.
16 . The kit of claim 15 , wherein the tumor is a breast tumor.