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Document URL: http://www.europa.com/~rsc/cancer/krebs46c.txt
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From:Science Vol. 104, No. 2700, 1946 p.302

Trophoblast Elements in Cancer

   In confirmation of the findings of Roffo (Bol. Inst. med. exp. Estud.
Cancer, 1944, 21, 419-588) that, when injected into immature white rats,
an extract of the blood or urine of cancer patients causes enlargement of
the uterus and the formation of corpora lutea in the female animals, we 
have obtained from cancer patients of both sexes, by urinary extraction,
preparations having pronounced estrogenic as well as gonadotropic
properties.  Nonmalignant, nonpregnant controls were negative.

   It is our conclusion on the basis of studies now in progress (Science,
1946, 103, 25), that the estrogenic factor (termed "steroid E" by Roffo)
arising from the definitive malignant elements is identical with the
steroids produced by the syncytial trophoblast of pregnancy (Jones, Gey,
and Gey. Johns Hopk. Hosp. Bull., 1943, 72, 23-38).  The only so-called
false positives observed by Roffo were those in which pregnancy urine was
used.  Moreover, 20 days after implanting human trophoblast into the eye
of a virgin doe, we found uterine and ovarian changes which duplicated
those reported above for the immature rat recipients of cancer urine (J.
clin. Endo-crinol., in press).

  It is well known that chorionepithelioma, genital as well as primary
extragenital in both sexes; many ovarian and most testicular cancers; the
chorionic (trophoblastic) or malignant phase of many teratomata; and even
some cases of carcinoma simplex are responsible for the presence of
chorionic (cytotrophoblastic) prolan in sufficient quantities in the blood
or urine to produce a positive Aschheim-Zondek reaction.  In these tumors
the prolan titer tends to vary directly with the concentration of
cytotrophoblast (Langhans cells), being almost beyond detection in the
absence of overt trophoblast.

  Using rodents as indicators, it is impossible to distinguish accurately
between anterior pituitary and chorionic prolans.  In pregnancy and in the
malignant tumors cited, the chorionic prolan is present in such excess of
pituitary prolan that diagnosis becomes a matter of quantitation.  In the
past, attempts to recover chorionic prolan from the blood or urine of all
cancer cases showing no *overt* trophoblast have been thwarted by cross-
reactions with pituitary prolan.  Employing the technics of chromatographic
adsorption (Katzman, Godfrid, Kain, and Doisy. J. biol.Chem., 1943, 148,
501-507) and the use of the African clawed toad (*Xenopus laevis*) as a
specific indicator of chorionic prolan, these obstacles are overcome.
Employing a combination of such technics, we have obtained egg extrusion
in *Xenopus laevis* through the injection of 1 cc. of the concentrate of
as little as 800 cc. of urine from nongenital cancer in the human male.
Controls of the same age were negative.

  Although sufficient determinations have not yet been made to warrant the
conclusion that specific steroids and/or cytotrophoblastic prolans are
present in all cases of cancer, our preliminary results would suggest this.

  In conclusion, it would appear significant that many of the most malignant
exhibitions of cancer are known to yield a readily detectable quantity of
gonadotropin, duplicated only by that produced by the trophoblast cell; that
now tumors of lesser malignancy are found to yield this same gonadotropin;
and, finally, that the only cell never observed in the benign state in the
male or, aside from the canalization of pregnancy, in the female is the
trophoblast cell.  Parallel to this is the finding in cancer of a steroid
duplicated only by the syncytial trophoblast.  These data would seem further
to substantiate the unitarian nature of all exhibitions of cancer and to
suggest the trophoblast elements (however masked morphologically) as the
constant malignant component.

ERNST T. KREBS, JR.
*University of California Medical School, San Francisco*

CHARLES GURCHOT
*San Francisco, California*
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