Research Article - Journal of Molecular Oncology Research (2018) Volume 2, Issue 1
hCG attenuates hyperglycosylated hCG-driven growth and invasion.
Laurence A. Cole*
USA hCG Reference Service, Angel Fire, NM 87710, USA
- *Corresponding Author:
- Laurence A. Cole
USA hCG Reference Service
Angel Fire, NM 87710, USA
E-mail: [email protected]
Accepted date: January 10, 2018
Citation: Cole LA. hCG attenuates hyperglycosylated hCG-driven growth and invasion. J Mol Oncol Res. 2018;2(1):13-20.
Objective: To determine the role of the hormone hCG in pregnancy, choriocarcinoma and cancer cell growth and invasion. Methods: Third trimester placenta cytotrophoblast primary cultures, two choriocarcinoma cell lines, and one trophoblastic cancer and 5 non-trophoblastic cancer cell lines. Results: Hyperglycosylated hCG promotes growth and invasion of normal pregnancy, 2 of 2 choriocarcinoma cell lines and 6 of 6 cancer cell lines. The hormone hCG attenuates or blocks growth and invasion in normal pregnancy, 2 of 2 choriocarcinoma and 6 of 6 cancer cell lines. Discussion: Cancer cells seemingly have adopted the hCG/LH receptor system. All cancers may be treated with hormone hCG to block and attenuate cancer growth, invasion and progression.
Pregnancy failures, Matrigel membranes, Hyperglycosylated
Human chorionic gonadotropin (hCG) is a glycoprotein hormone produced by placental cells. hCG is in fact two separate independent molecules that are 97% structurally the same [1,2]. They have identical a- and β-subunit amino acid sequence [1,2], they share identical N-linked oligosaccharides, and very different type 1 and type 2 O-linked oligosaccharides on the C-terminal peptide of the β-subunit . There is the hormone hCG produced by fused syncytiotrophoblast cells that binds and acts on a luteinizing hormone (LH)/hCG joint receptor on cytotrophoblast cells and on maternal uterine tissues and maternal corpus luteal cells [3,4]. And there is the autocrine hyperglycosylated hCG which is made by cytotrophoblast cells which has no action on the LH/hCG hormone receptor and antagonizes a transforming growth factor-β (TGF-β) receptor on cytotrophoblast cells [5-7].
It has been well established that hyperglycosylated hCG drives placental invasion as in implantation of pregnancy [8-10], and that it also drives choriocarcinoma cell growth and invasion and cancer cell grow and invasion or malignancy [8-12]. It achieves this through promoting the transferring growth factor- β (TGF-β) receptor and promoting production of collagenases and metalloproteinases [5-7,13-15].
Materials and Methods
Purified cytotrophoblast cells from term pregnancies were kindly provided by Harvey Kliman at Yale University in Dulbecco’s High Glucose medium with 10% fetal calf serum (DHG-10%). Cytotrophoblast cell were purified by Percoll density centrifugation from trypsin dispersed term pregnancy villous trophoblast tissue using the methods used by Harvey Kliman previously .
JAR and JEG-3 choriocarcinoma cell lines, NTERA testicular germ cell cancer cell line, ScaBER bladder carcinoma cells line, T24 epithelial bladder cancer cell line, CaSki epidermoid cervical cancer cell line, Hec-1-a endometrial adenocarcinoma cell line, and KLE endometrial aneuploid cancer cell line were all cultured to 70% flask confluency in T75 flasks with DHG-10% medium.
All flasks were cultured with supplemental hormone hCG (recombinant, Sigma, St. Louis MO) and supplemental hyperglycosylated hCG (batch C5) at 10 ng/ml, 100 ng/ml and 1,000 ng/ml using the same medium.
Total hCG (all forms of hCG, including hCG-H, hCG and their free β-subunits) were measured using the Siemens Healthineers Inc. (New York, NY) Immulite hCG assay on the Immulite automated immunoassay platform. This assay was calibrated with recombinant hormone hCG in ng/ml. The sensitivity of this assay was 0.091 ng/ml, the equivalent of 1.0 mIU/ml assuming that 1 ng/ml=11 mIU/ml .
Hyperglycosylated hCG was measured using the established B152 microtiter plate immunometric assay , nicked hCG using the B151 microtiter plate immunometric assay, free β- subunit using the FBT11 microtiter plate immunometric assay  and β-core fragment using the B210 microtiter plate immunometric assay .
Matrigel invasion assay
Matrigel membranes were processed and percentage invasion calculated as suggested by the manufacturer in package inserts. Briefly, membranes are rehydrated in DHG-10% in the incubator for 2 h before use. Membranes and control inserts are then plated (25,000 cells in 0.5 medium per plate). Plates are cultured for 24 h, and membranes removed from the inserts using a scalpel. Membranes are transferred to a slide using Cytoseal mounting medium (Stephens Scientific Inc., Riverdale NJ), exposing the under surface or the invaded cells. Cells are stained with DIF-Quick Stain (IMEB Inc., Chicago IL) to mark nuclei. Invaded cells are counted at 5 marked places, and the count averaged. Cell penetration or invasion of membranes is directly compared to that of correspondingly cultured control inserts and the percentage invasion is calculated using the formula provided by the manufacturer.
USA hCG reference service customers
All customers of the USA hCG Reference Service completed a form giving the USA hCG Reference Service permission to blindly publish total hCG and hyperglycosylated hCG results, and to use them for research. Three clients refused this option, their results are omitted from this report.
Serial first morning urine samples were collected from 149 volunteer women all married, of mixed race (111 White, 28 Hispanic, 10 African American) and mixed age (range 18-36, mean 27.8 years) and all agreed to be actively involved in intercourse, particularly around the mid-cycle of the menstrual period, or all were eager to achieve to reach pregnancy. All female volunteers lived in Albuquerque NM. Urine collection was carefully monitored by University of New Mexico Human Research Review Committee (HRRC) the institutional review board (IRB) in approved application 04-132 signed 7/02/04.
In each case first morning urines were collected daily, and stored in supplied storage cups and immediately frozen in their home freezer. Urines were picked up at homes twice weekly and daily LH, total hCG and hyperglycosylated was measured. Women received $100 monthly for compensation for collecting daily first morning urines. All urine collection was sponsored by Church and Dwight Inc. and eventual pregnancy urines used were collected and sent to Church and Dwight to evaluate home pregnancy testing devices. Daily pregnancy urines were tested for total hCG and hyperglycosylated hCG from 2 days prior to implantation to 34 days of gestation. Church and Dwight Inc. approved this report as a side project.
The day of implantation of pregnancy was assumed as the day of production of the hormone hCG (sensitivity 0.091 ng/ml=1 mIU/ml) as proposed by Wilcox et al. .
When normal placenta cytotrophoblast primary cells were cultured in Matrigel invasion chambers, cells invaded the plasma membrane chambers driven by the hyperglycosylated hCG produced by the cell line (Table 1, control cultures). They invaded by 41 ± 12%. When hyperglycosylated hCG was added to normal placenta cytotrophoblast cells, 10 ng/ml, invasion was extended to 66 ± 13%, and when 100 ng/ml was added invasion was extended to 86 ± 12%. The hormone hCG very much undid or attenuated this invasion, the hormone hCG, 10 ng/ml, diminished invasion to 34 ± 9%, and 100 ng/ml diminished invasion to 26 ± 11% (Table 1).
|Penetration of Matrigel Membranes, mean ± SD|
|Pregnancy term placenta primary cytotrophoblast cells|
|Control cultures, no additive||41 ± 12%|
|hCG-H, 10 ng/ml||66 ± 13%a|
|hCG-H, 100 ng/ml||86 ± 12%a|
|Hormone hCG, 10 ng/ml||34 ± 9%|
|Hormone hCG, 100 ng/ml||26 ± 11%a|
|JEG-3 Choriocarcinoma cytotrophoblast cells cells|
|Control cultures, no additive||48 ± 11%|
|hCG-H, 10 ng/ml||68 ± 14%a|
|hCG-H, 100 ng/ml||88 ± 6%a|
|Hormone hCG, 10 ng/ml||42 ± 9%|
|Hormone hCG, 100 ng/ml||38 ± 3%a|
|JAr Choriocarcinoma cytotrophoblast cells|
|Control culture, no additive||42 ±13%|
|hCG-H, 10 ng/ml||70 ± 11%a|
|hCG-H, 100 ng/ml||86 ±10%a|
|Hormone hCG, 10 ng/ml||32 ± 10%|
|Hormone hCG, 100 ng/ml||26 ± 8%a|
|aA significant difference was observed by t test compared to control, P > 0.05|
Table 1: Effect of hyperglycosylated hCG (hCG-H) and the hormone hCG on cell invasion on Matrigel membranes. Cells were separately cultured for 24 hours (5000 cells) on Matrigel basement membranes and control inserts in triplicate. Concentration of the hyperglycosylated hCG and the hormone hCG added to enhance or diminish invasion were 10 ng/ml and 100 ng/ml. The underside of Matrigel basement membranes, containing penetrated or invaded cells, was stained and counted. Cell penetration was compared with that of control inserts. Evperiment performed in quadruplicate. The percentage penetration or invasion was calculated using the formula described by the manufacturer.
I next investigated hyperglycosylated hCG and hormone hCG action on primary cytotrophoblast cell growth (Table 2). Control cultures grew over 24 h to 543,000 ± 78,000 cells. When media was supplemented with 10 ng/ml hyperglycosylated hCG cells grew to 783,000 ± 67,000 (+41%) cells, when supplemented with 100 ng/ml they grew to 875,000 ± 72,000 cells (+61%). The hormone hCG very much undid or attenuated cell growth, 10 ng/ml, diminished growth to 424,000 ± 7,700 (-22%), 100 ng/ml diminished growth to 260,000 ± 11,000 (-52%) and 1,000 ng/ml diminished growth to 136,000 ± 10,000 (-75%) (Table 2).
|Control 0 ng/ml||hCG-H 10 ng/ml||hCG-H 100 ng/ml||hCG 10 ng/ml||hCG 100 ng/ml||hCG 1000 ng/ml|
|Pregnancy term placenta primary cytotrophoblast cells||543,000 ± 78,000||763,000 ± 67,000||873,000 ± 72,000||424,000 ± 7,700||260,000 ± 11,000||136,000 ± 10,000|
|Jar choriocarcinoma||428,000 ± 45,000||478,000 ± 59,000||556,000 ± 33,000||343,000 ± 31,000||312,000 ± 57,000||127,000 ± 6,000|
|JEG-3 choriocarcinoma||829,000 ± 45,000||912,000 ± 87,000||1,061,000 ± 28,000||698,000 ± 119,000||504,000 ± 71,000||361,000 ± 32,000|
|NTERA testicular germ cell malignancy||446,000 ± 83,000||526,000 ± 18,000||589,000 ± 27,000||147,000 ± 14,000||134,000 ± 4,000||131,000 ± 4,000|
|ScaBER bladder carcinoma||492,000 ± 10,000||738,000 ± 45,000||772,000 ± 19,000||400,000 ± 40,000||235,000 ± 17,000||199,000 ± 11,000|
|T24 Epithelial bladder cancer||1,359,000 ± 60,000||1,494,900 ± 78,000||1,739,000 ± 227,000||1,150,000 ± 61,000||1,054,000 ± 35,000||473,000 ± 36,000|
|CaSki epidermoid cervical cancer||839,000 ± 43,000||988,000 ± 82,000||1,256,000 + 125,000||736,000 ± 55,000||665,000 ± 22,000||479,000 ± 31,000|
|KLE endometrial aneuploid cancer||602,000 ± 57,000||704,000 ± 34,000||795,000 ± 7,000||451,000 ± 36,000||444,000 ± 18,000||400,000 ± 22,000|
|Hec-1-a endometrial adenocarcinoma||578,000 ± 63,000||798,000 ± 58,000||959,000 ± 44,000||525,000 ± 58,000||350,000 ± 40,000||259,000 ± 18,000|
|aA significant difference was observed by t test compared to control, P > 0.05|
Table 2: Promotion of cell growth by hyperglycosylated hCG, blockage or attenuation of cell growth by the hormone hCG. The abbreviation hCGH is hyperglycosylated hCG, and hCG is the hormone hCG. Experiment performed in quadruplicate.
It was concluded that hyperglycosylated hCG expanded primary placental cytotrophoblast cell growth and invasion, and that the hormone hCG attenuated placenta cytotrophoblast cell growth and invasion.
A total of 149 women volunteers tried to get pregnant over a 5 menstrual period, time. Of these 117 women achieved pregnancy, 73 achieved term pregnancy and childbirth, nineteen achieved a spontaneous abortion or miscarriage in the first trimester of pregnancy, 21 achieved a biochemical pregnancy or a miscarriage two or three days after implantation and 4 achieved an ectopic pregnancy or failing pregnancy outside of the uterus (Table 3).
|Term/Childbirth pregnancy, n=73||Spontaneous abortion pregnancy (n=19)||Biochemical pregnancy (N=21)||Ectopic pregnancy (n=4)|
Table 3: Proportion hyperglycosylated hCG in 117 pregnancies on the day of implantation, 73 term/childbirth pregnancies, 19 first trimester spontaneous abortion/miscarriage, 21 biochemical and 4 ectopic pregnancies. The abbreviation T-hCG is total hCG and H-hCG is hyperglycosylated hCG.
The proportion hCG (hyperglycosylated hCG/ hyperglycosylated hCG+hormone hCG) forms among those with term/childbirth pregnancy was 69 of 73 (95%) >40%, mean is 112% (Table 3). The proportion hCG forms among those with spontaneous abortion of miscarriage pregnancies was 0 of 19 (0%) pregnancies >40%, mean is 14% indicating that no pregnancy made enough hyperglycosylated hCG for implantation, or all too much hCG for implantation. The proportion hCG forms among the 21 with biochemical pregnancies, 0 of 21 (0%) pregnancies made >40%, mean is 2.6% indicating once again that none made enough hyperglycosylated hCG or made too much hCG for implantation. Again with ectopic pregnancy 0 of 4 (0%) made >40% hyperglycosylated hCG needed for implantation (Table 3). The proportion hyperglycosylated hCG in these 117 pregnancies, 0 of 44 (0%) failing pregnancies produced >40% hyperglycosylated hCG, clearly shows the importance of sufficient hyperglycosylated hCG and the importance of not too much attenuating hCG for implantation to be complete.
Does hyperglycosylated hCG drive invasion and the hormone hCG attenuate invasion in choriocarcinoma? As shown in Table 1, using two choriocarcinoma cell lines, Jar and JEG-3, hyperglycosylated hCG drives invasion. In JEG-3 cells 10 ng/ml and 100 ng/ml hyperglycosylated hCG drove cells from 48 ± 11% invasion to 68 ± 14% to 88 ± 6%, while 10 ng/ml and 100 ng/ml hormone hCG diminished cells from 48 ± 11% to 42 ± 9% to 38 ± 3%. In Jar cells 10ng/ml and 100 ng/ml hyperglycosylated hCG drove cells from 42 ± 13% invasion to 70 ± 11% to 86 ± 10%, while 10 ng/ml and 100 ng/ml hormone hCG diminished cells from 42 ± 13% to 32 ± 10% to 26 ± 8%.
In terms of choriocarcinoma cell growth, in JEG-3 cells, hyperglycosylated hCG, 10 ng/ml and 100 ng/ml, developed cells by +10% and +28% (Table 2). Hormone hCG, 10 ng/ml, 100 ng/ml and 1,000 ng/ml diminished cell growth -16%, -39%, and -56%. Looking at Jar choriocarcinoma cells, hyperglycosylated hCG, 10 ng/ml and 100 ng/ml, developed cells by +12% and +30% (Table 2). Hormone hCG, 10 ng/ml, 100 ng/ml and 1,000 ng/ml diminished cell growth -20%, -27% and -70%.
Clearly, hyperglycosylated hCG promotes cell invasion and cell growth while the hormone hCG attenuates or blocks cell invasion and cell growth in choriocarcinoma cells as well as in normal pregnancy tissue.
The USA hCG Reference Service has seen 47 choriocarcinoma cases from around the world. All bloods were tested for the concentration of the hormone hCG and the autocrine hyperglycosylated hCG (Table 4). As found, the diagnoses made by the USA hCG Reference Service could be defined as Maximally Aggressive Choriocarcinoma (81%-100% hyperglycosylated hCG), Aggressive Choriocarcinoma (41-80% hyperglycosylated hCG), Minimally Aggressive Choriocarcinoma (1%-40% hyperglycosylated hCG), and Quiescent Choriocarcinoma (<1% hyperglycosylated hCG). Just based on the percent hyperglycosylated hCG (hyperglycosylated hCG/hyperglycosylated hCG + hormone hCG) the aggressiveness of choriocarcinoma can be accurately defined (Table 4) . Interestingly, the percent hyperglycosylated hCG as a clinical parameter exactly correlated with the cancer doubling rate (weeks) as a parameter, r2 = 0.996. As such, the measurement of percent hyperglycosylated hCG is an alternative measurement of cancer aggressiveness to, difficult to determine cancer doubling rate, that can be used by treating physicians.
|Age||Diagnosis made by USA hCG Reference Service||Total hCG (mIU/ml)||hCG-H (ng/ml)||hCG-H (mIU/ml)||Percent hCG-H hCG-H/hCG (%)||Cancer Doubling rate (weeks)|
|25||Maximally Aggressive Choriocarcinoma||40256||4400||48400||100%||2.6|
|32||Maximally Aggressive Choriocarcinoma||80400||8050||88550||100%||3|
|21||Maximally Aggressive Choriocarcinoma||314000||429000||390000||100%||<2|
|34||Maximally Aggressive Choriocarcinoma||399500||37270||401000||100%||<2|
|21||Maximally Aggressive Choriocarcinoma||932000||85090||936000||100%||<2|
|19||Maximally Aggressive Choriocarcinoma||50053||4333||47663||95%||Not determined|
|34||Maximally Aggressive Choriocarcinoma||116620||10011||110121||94%||<2|
|37||Maximally Aggressive Choriocarcinoma||596000||50931||560240||94%||5.5|
|N/A||Maximally Aggressive Choriocarcinoma||37500||3110||34210||91%||2.4|
|35||Maximally Aggressive Choriocarcinoma||141627||11034||121374||86%||<2|
|26||Maximally Aggressive Choriocarcinoma||45000||3400||37400||83%||<2|
|N/A||Maximally Aggressive Choriocarcinoma||40644||3012||33132||82%||2.6|
|Mean ± SD||94% ± 6.9%||2.57 ± 1.09|
|N/A||Aggressive choriocarcinoma||80699||5560||61160||76%||Not determined|
|Mean ± SD||60% ± 13%||3.85 ± 0.58|
|37||Minimally Aggressive choriocarcinoma||27688||982||10802||39%||5.5|
|27||Minimally Aggressive choriocarcinoma||440||15.1||166.1||38%||5.2|
|42||Minimally Aggressive choriocarcinoma||542||17||187||35%||4.5|
|50||Minimally Aggressive choriocarcinoma||1596||42||462||29%||Not determined|
|29||Minimally Aggressive choriocarcinoma||214||5.6||61.6||29%||5.5|
|32||Minimally Aggressive choriocarcinoma||5290||112||1232||23%||4|
|30||Minimally Aggressive choriocarcinoma||20440||4025||44275||22%||5|
|31||Minimally Aggressive choriocarcinoma||639||11.7||128.7||20%||5.5|
|37||Minimally Aggressive choriocarcinoma||735||7.8||85.8||12%||>6|
|46||Minimally Aggressive choriocarcinoma||238||2||22||9.2%||>6|
|Mean ± SD||26 ± 10%||5.20 ± 0.66|
|26||Quiescent choriocarcinoma||3.4||Not detected||<1%||>6|
|24||Quiescent choriocarcinoma||7.2||Not detected||<1%||>6|
|17||Quiescent choriocarcinoma||11||Not detected||<1%||>6|
|23||Quiescent choriocarcinoma||7.8||Not detected||<1%||>6|
|27||Quiescent choriocarcinoma||3.3||Not detected||<1%||>6|
|32||Quiescent choriocarcinoma||17||Not detected||<1%||>6|
|35||Quiescent choriocarcinoma||20||Not detected||<1%||>6|
|Mean ± SD||<1 ± 0.013%||5.93 ± 0.17|
|36||Recurrent quiescent choriocarcinoma||28||1.3||14.3||51%||Not determined|
|55||Recurrent quiescent choriocarcinoma||22||1||11||50.0%||3.5|
|41||Recurrent quiescent choriocarcinoma||73||0.92||10.12||13.8%||Not determined|
|38||Recurrent quiescent choriocarcinoma||66||0.75||8.25||12.5%||4.5|
|19||Recurrent quiescent choriocarcinoma||224||2||19||8.5%||5|
|Mean ± SD||26 ± 21%||4.37 ± 0.63|
Table 4: Serum samples from 47 choriocarcinoma cases. hCG-H is the B152 hyperglycosylated hCG result in ng/ml, converted to hCG equivalents mIU/ml (X11) and the proportion hCG-H of total hCG (% hCG-H). The cancer doubling rate is the consulting physician’s estimated time for the cancer mass to double.
It is concluded that in choriocarcinoma, exactly like pregnancy [1,2], that cancer invasion and growth is controlled by hyperglycosylated hCG, which promotes growth and invasion, and the hormone hCG, which attenuates growth and invasion. Percent hyperglycosylated hCG is an alternative measurement of cancer aggressiveness, to cancer doubling rate, that can be used with choriocarcinoma cases.
I considered other cancers, do they respond to the hormone hCG? As shown in Table 2, NTERA testicular germ cell cancer was promoted to grow by +18% and +32% by hyperglycosylated hCG, and diminished -67%, -70% and -70% by the hormone hCG. ScaBER bladder cancer was promoted to grow by +50% and +56% by hyperglycosylated hCG, and diminished -19%, -52% and -60% by the hormone hCG. T24 epithelial bladder cancer was promoted to grow by +10% and +29% by hyperglycosylated hCG, and diminished -15%, -22% and -66% by the hormone hCG. CaSki epidermoid cervical cancer was promoted to grow by +17% and +32% by hyperglycosylated hCG, and diminished -12%, -21% and -53% by the hormone hCG. KLE endometrial aneuploid cancer was promoted to grow by +17% and +32% by hyperglycosylated hCG, and diminished -25%, -26% and -34% by the hormone hCG. HEC-1-a endometrial adenocarcinoma was promoted to grow by +38% and +66% by hyperglycosylated hCG, and diminished -9%, -39% and -55% by the hormone hCG.
Overall, cancers were promoted to grow by hyperglycosylated hCG +10% to +66%, and were declined by the hormone hCG -9% to -70%. Hyperglycosylated hCG promotes cell growth in pregnancy, choriocarcinoma and cancer, and the hormone hCG attenuates or blocks growth in pregnancy, choriocarcinoma and cancer.
Very clearly, hyperglycosylated hCG promotes cell growth and cell invasion in pregnancy, choriocarcinoma and cancer cases. Hyperglycosylated hCG promotes malignancy . The hormone hCG attenuates or blocks cell invasion and cell growth in pregnancy, choriocarcinoma and cancer cases.
It is inferred that the hCG/LH receptor is active in pregnancy, choriocarcinoma and cancer cases. It is probable, that when cells gather the hCG β-subunit gene as in carcinogenesis or transformation that the hCG/LH receptor gene may be directly connected, or turned on. Thus all cancer cells, just as they steal hCG β-subunit for malignancy , may get the hCG/LH receptor gene and thus respond to hCG.
Just as the hormone hCG attenuates or controls hyperglycosylated hCG-led invasion and growth in pregnancy, it may be used to attenuate or control malignancy in cancer patients, to control cancer while awaiting appropriate therapy or to suppress cancer in advanced cancer patients.
The hormone hCG has very little side effects in the postmenopausal women, and only promotes sexuality or testosterone production in the man. The hormone hCG might be administered intra-muscularly twice weekly to the patient with terminal cancer, to keep the cancer appropriately suppressed, and to achieve longevity with terminal cancer. Proportion hyperglycosylated hCG (hyperglycosylated hCG/ hyperglycosylated hCG+hormone hCG) might be useful to measure cancer aggressiveness status in choriocarcinoma cases.
Conflicts of Interest
The author declares that there are no conflicts of interest.
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